Parallel combinatorial approach to the discovery and optimization of catalysts and uses thereof

ABSTRACT

The present invention provides methods and compositions, i.e. synthetic libraries of candidate compounds, useful in the discovery and optimization of compounds which catalyze at least one chemical transformation. In certain instances, the subject compounds catalyze a chemoselective, regioselective, stereoselective or enantioselective transformation.

BACKGROUND OF THE INVENTION

[0001] During the course of a chemical reaction, the reactants mayundergo a series of transformations comprising passing throughtransition states (local energy maxima) and intermediates (local energyminima) until the products are formed. In molecular terms, thesetransformations reflect changes in bond lengths, angles, etc. Theevolution from reactants to products, in a reaction that does not passthrough any intermediates, may be viewed simply as involving formationof a transition state which decomposes to yield the products. Theoverall rate of this simple reaction can be expressed in terms of theequilibrium constants characterizing the equilibria between thereactants, the transition state, and the products.

[0002] Under these circumstances, catalysis can be regarded as astabilization of the transition state for the reaction. A catalyst is asubstance that increases the rate of a reaction, by lowering the energyof the transition state, and is recovered substantially unchanged at theend of the reaction. Although the catalyst is not consumed, it is agreedthat the catalyst participates in the reaction. Despite the commercialimportance of catalysis, major limitations are associated with bothenzymatic and non-enzymatic catalysis. Economically-viable, efficient,and reliable transition metal-catalyzed processes are relatively few innumber. The industrial utility of such processes may be diminished bytheir high operating costs, the incompatibility of the requisitereagents with environmental or toxicological imperatives, ordifficulties associated with the isolation and purification of thedesired products. Furthermore, non-enzymatic catalysts are not yet knownfor many important chemical reactions. Enzymatic catalysis depends onthe existence and discovery of naturally occurring enzymes with theappropriate specificity and catalytic function to perform a particularreaction. Enzymes are not known for many, if not most, chemicaltransformations.

[0003] The immune system has been shown to have the ability to generatevarious de novo antibody catalysts. In short, antibodies are elicited toa hapten designed to mimic the transition state of the reaction ofinterest; the resulting antibodies are then screened for catalyticactivity. Advances in the design of transition state analogues, and inthe methods of generation and screening of antibodies to those analogueshave resulted in catalytic antibodies for a wide range of chemicaltransformations (cf. inter alia: Romesberg et al. Science 1998, 279,1929-1933; Heine et al. Science 1998, 279, 1934-1940; and referencestherein). Of course, an approach to catalysis based upon catalyticantibodies is limited in scope. First, this approach presupposes aknowledge of the transition state for a transformation. Second, it maybe difficult or impossible to synthesize the required transition stateanalogue(s). Finally, antibodies are proteins and are subject to thelimitations associated with polypeptides, e.g. susceptibility toproteolytic degradation, high molecular weight, and poor solubilitycharacteristics.

[0004] The present invention overcomes the aforementioned limitations byproviding a novel approach to the discovery and optimization of newcatalysts. The invention provides a parallel combinatorial method forthe preparation, evaluation, and optimization of organic molecules asconvenient, readily obtainable and inexpensive catalysts possessing ahigh degree of specificity and efficiency. In certain embodiments,catalysts that do not rely on a transition metal ion for activity areprovided. In other embodiments, this invention is useful in increasingthe rate of chemical reactions which can also be catalyzed by enzymessuch as oxidoreductases, transferases, hydrolases, lyases, isomerasesand ligases. In certain embodiments, this invention is useful inincreasing the rate of chemical reactions for which no catalysts, eitherenzymatic or non-enzymatic, are known presently. Such reactions include,among others, oxidations, reductions, additions, condensations,eliminations, substitutions, cleavages, rearrangements, and kineticresolutions.

[0005] In accordance with this invention, the subject catalysts mayincrease the rate of a chemical reaction by more than a factor of onehundred, preferably more than a factor of one thousand, and mostpreferably more than a factor of ten thousand.

[0006] Furthermore, research into the relationship between catalyststructure and catalytic properties is a central theme in such active anddisparate fields as asymmetric synthesis, medicinal chemistry, processchemistry, selective catalysis, bioremediation, sensor discovery anddevelopment, bioorganic chemistry, and bioinorganic chemistry. Thenumerous advances made recently in these fields underscore the utilityof catalysts with well-defined structural, electronic and/orstereochemical features. However, the de novo rational design of suchcatalysts remains extremely challenging, if not unattainable at present,especially if novel physical and chemical properties are sought. In thiscontext, a systematic method for the expedient generation of new classesof catalysts will be of great value.

[0007] Immobilization, or isolation within a semi-permeable membrane, ofa catalyst would enable the reuse of a catalyst without the need fortedious isolation and purification protocols; additionally, thisapproach may help avoid the common problems of gradual degradationand/or fouling of catalysts. In this regard, Kobayashi and Nagayamarecently disclosed the development of immobilized, microencapsulatedLewis acid catalysts that are both recoverable and reusable (J. Am.Chem. Soc. 1998, 120, 2985). Furthermore, these researchers found thatin some cases the activity of the encapsulated catalysts is even greaterthan that of the non-encapsulated catalysts. Examples of the activityand reuse of enzymes contained within semi-permeable membranes have beenreported by Whitesides, Bednarski, and others. The catalysts of thepresent invention may be immobilized and/or isolated withinsemi-permeable membranes and used as such.

SUMMARY OF THE INVENTION

[0008] The present invention provides methods and compositions, i.e.synthetic libraries of compounds, for identifying novel compounds whichcatalyze at least one chemical transformation. The subject methodcomprises: (a) chemically synthesizing a variegated library of candidatecatalysts; and (b) screening the library of candidate catalysts toisolate/identify those members that catalyze a given reaction. Utilizingthe techniques of combinatorial chemistry, e.g., directcharacterization, encoding, spatially addressing and/or deconvolution,the molecular identity of individual members of the library of candidatecatalysts can be ascertained in a screening format. Another aspect ofthe present invention pertains to kits for carrying out the instantmethod. Still another aspect of the present invention providescompositions including one or more of the catalysts identified by theinstant method.

BRIEF DESCRIPTION OF THE FIGURES

[0009]FIG. 1 depicts a generalized structure of a potential catalystsystem.

[0010]FIG. 2 depicts the structures of the members of Libraries 1-3.

[0011]FIG. 3 depicts the enantioselectivities observed in the catalyzedStrecker reaction as a function of the structure of the metal-freecatalyst utilized.

[0012]FIG. 4 depicts the enantioselectivities observed in the catalyzedStrecker reaction utilizing members of Library 3.

[0013]FIG. 5 depicts schematically a combinatorial strategy for thegeneration of libraries of potential catalysts.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The synthesis and screening of combinatorial libraries is avalidated strategy for the identification and study of ligand-receptorinteractions. For recent reviews on strategies for the synthesis ofsmall-molecule libraries, see: Thompson et al. (1996) Chem Rev. 96:555;Armstrong et al. (1996) Acc. Chem. Res. 29:123; Gordon et al. (1994) J.Med. Chem. 37:1385. For combinatorial approaches to the study ofligand-receptor interactions, see Still et al. (1996) Acc. Chem. Res.29:155, and references therein; Yu et al. (1994) Cell 76:933; Combs etal. (1996) J. Am. Chem. Soc. 118:287; Zuckermann et al. (1994) J. Med.Chem. 37:2678; Wang et al. (1995) J. Med. Chem. 38:2995; Campbell et al.(1995) J. Am. Chem. Soc. 117:5381. In this context, combinatorialsystems have allowed many structural changes to be examinedsimultaneously, thus allowing an evaluation of, for example, synergisticeffects in recognition events. Since the stability of a transitionstate-catalyst complex-is similarly dependent on numerous interrelatedvariables, including but limited to the steric and electroniccharacteristics of the catalyst and substrate, combinatorial chemistrycould also provide a powerful approach for discovering new classes ofcatalysts, and/or new members of known classes of catalysts. Forexample, spatially addressed synthetic libraries have been applied withsuccess for the identification of selective catalysts (Burgess et al.(1996) Angew. Chem. Int. Ed. Engl. 35:220; and Reetz et al. (1997)Angew. Chem. Int. Ed. Engl. 36:2830).

[0015] I. Overview.

[0016] The method of the present invention is a fundamentally differentapproach, based on parallel combinatorial synthesis schemes, todiscovering and optimizing catalysts for chemical transformations.Rather than begin with a predefined catalytic structure, the subjectmethod involves the generation of libraries of potential catalysts fromdiverse sets of functional groups and conformational restrictions; thisapproach results in a wide range of potentially catalytic environments.As described below, we have demonstrated that the subject combinatoriallibraries can be successfully applied to the identification andoptimization of novel catalysts, e.g. for the addition of nucleophilesto π-bonds. Moreover, the structural features that lead to catalysis,and selectivity where relevant, are quite unanticipated, and comprisenon-intuitive synergistic effects between structural elements of thecatalysts.

[0017] In its most general embodiment, the process of the present methodcomprises: (a) the chemical synthesis of a variegated library ofpotential catalysts from an assortment of structural elements comprisingvarious functional groups and turn elements; and (b) screening thelibrary of catalysts to identify/isolate those members that catalyze agiven transformation. Through the application of the techniques ofcombinatorial chemistry, e.g., encoding, spatially addressing, massspectroscopy and/or deconvolution, libraries of potential catalysts canbe synthesized by batch processes and, perhaps more importantly, themolecular identity of the individual members of the library can beascertained in a screening format. It will be understood that once alibrary of potential catalysts is constructed, the library can bescreened for catalytic activity in any number of chemicaltransformations.

[0018] Moreover, while for ease of reading the application will referpredominantly to synthetic organic reactions as the preferredtransformations for which the potential catalysts are screened, thoseskilled in the art will appreciate that the subject method and librariesmay be used to screen for catalysts that exert their influence on othertypes of transformations, e.g., photochemical energy transfers,inorganic redox reactions, synthetic inorganic reactions, andpolymerizations.

[0019] As described in greater detail below, there are a wide range ofapplications for the novel catalysts identified by the subject method.For example, in one embodiment, the subject libraries of catalysts maybe generated via the present method with the goal of discovering andoptimizing a catalyst for a particular reaction. The selectivity of apotential catalyst can be exploited to transform a single component,e.g. molecule, or stereoisomer, or a subset of the components of acomplex mixture. For instance, such selectivity can be utilized in thekinetic resolution of racemic mixtures of enantiomers, or in theenantioselective transformations of meso reactants. Furthermore, if thetransformation catalyzed by a catalyst of the subject method isaccompanied by a detectable event, e.g. the formation of a precipitate,the evolution of a gas, or the emission of a photon, the combination ofthe catalyst and the detectable event may form the basis of a test forthe presence, in a sample or a complex mixture, of thecatalyst'substrate. In a preferred embodiment, a catalyst of the subjectmethod which catalyzed reaction is accompanied by a detectable eventforms the basis of a sensor for the presence, and even more preferablyfor the quantification, of the substrate in a sample. In certainembodiments, the catalysts of the present invention are immobilizedand/or isolated within semi-permeable membranes and used as such;catalysts provided in this manner may be reused simply by removal fromthe reaction mixture of the solid support to which they are attached, orby removal of the semi-permeable membrane in which they areencapsulated, followed by simple rinsing and the like, and immersion inanother solution of reactants.

[0020] In general, the modular components exploited in the subjectmethod are selected to provide potential catalysts capable of increasingthe rate of formation of a product from one or more substrates, e.g.increasing the rate of an intramolecular or intermolecular reactionrelative to its rate in the absence of the catalyst. This rateenhancement may involve a role for the catalyst as, for example, ageneral base or general acid catalyst, an electrostatic catalyst, or anucleophilic catalyst or other type of covalent catalyst. In oneembodiment, catalysts of the present invention catalyze a reaction bylowering the energy of a transition state for the reaction of interest,such as by binding and stabilizing the transition state of thetransformation of choice. The selection of the modular componentsutilized in the subject method will depend upon such factors as theirchemical stability, their availability, the level of selectivity soughtin the reaction to be catalyzed, the presence of asymmetric centers, thepresence of structural elements either know to, or anticipated to,contribute to the creation of a viable catalytic site, and issues ofultimate catalyst solubility.

[0021] Strategies for the combination of the modular components to givecatalyst libraries are formulated based, in part, on the various factorsinferred to have been important in structure-function analyses ofestablished catalysts, including enzymes and non-enzymatic catalysts.For example, in preferred embodiments the library will be derived toinclude potential catalysts having functional groups capable ofinteracting, covalently or non-covalently, with a substrate, transitionstate, and/or a product of a desired reaction. Such functional groupswill often include heteroatoms such as nitrogen, oxygen, sulfur, andphosphorus. It will be understood that the modular components mayinclude side-chains or pendant groups capable of interacting with asubstrate.

[0022] Viable catalysts typically have more than one contact point witha substrate, and the libraries of potential catalysts is synthesizedaccordingly. For example, the catalysts of the invention are preferablycapable of associating with the substrate via at least two contactpoints, e.g. by hydrogen bonding, electrostatic interactions,hydrophobic interactions, and/or covalent interactions. For catalystscapable of spatial recognition, e.g., discrimination of diastereomers orenantiomers, at least two contact points between the catalyst and thesubstrate will generally be required.

[0023] In preferred embodiments, catalysts are synthesized to provide apredetermined degree of selectivity in the transformation catalyzed.Thus, for example, in certain embodiments, catalysts are capable ofkinetic resolution of enantiomers, e.g. catalyzing the reaction of oneenantiomer of a substrate in preference to the second enantiomer. Highlevels of chemo-, regio-and/or stereo-selectivity may be attained byappropriate choice of modular components for construction of a libraryof catalysts. Thus, catalysts can be synthesized and selected which arehighly selective for only a single substrate, or stereoisomer thereof,in a mixture of potential substrates, or stereoisomers thereof.

[0024] In preferred embodiments, a given library of potential catalystsincludes at least 10^(2,) more preferably 10³, 10⁴, 10⁵, 10⁶ or even 10⁷different potential catalysts. The library may, as appropriate, includepotential bidentate, tridentate, tetradentate and/or even higher ordermetal-chelating ligands. Preferably each potential catalyst, subsequentto being freed from the solid support, has a molecular weight less than7500 amu, more preferably less than 5000, 2500 or even 1000 amu, andeven more preferably less than 500 amu.

[0025] II. Definitions

[0026] For convenience, certain terms employed in the specification andappended claims are collected here.

[0027] The terms “Lewis base” and “Lewis basic” are recognized in theart, and refer to a chemical moiety capable of donating a pair ofelectrons under certain reaction conditions. Examples of Lewis basicmoieties include uncharged compounds such as alcohols, thiols, andamines, and charged moieties such as alkoxides, thiolates, carbanions,and a variety of other organic anions.

[0028] The terms “Lewis acid” and “Lewis acidic” are art-recognized andrefer to chemical moieties which can accept a pair of electrons from aLewis base as defined above.

[0029] The term “electron-withdrawing group” is recognized in the art,and denotes the tendency of a substituent to attract valence electronsfrom neighboring atoms, i.e., the substituent is electronegative withrespect to neighboring atoms. A quantification of the level ofelectron-withdrawing capability is given by the Hammett sigma (σ)constant. This well known constant is described in many references, forinstance, J. March, Advanced Organic Chemistry, McGraw Hill BookCompany, New York, (1977 edition) pp. 251-259. The Hammett constantvalues are generally negative for electron donating groups (σ[P]=-0.66for NH₂) and positive for electron withdrawing groups (σ[P]=0.78 for anitro group), σ[P] indicating para substitution. Exemplaryelectron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl,trifluoromethyl, —CN, chloride, and the like. Exemplaryelectron-donating groups include amino, methoxy, and the like.

[0030] The term “catalyst” refers to a substance the presence of whichincreases the rate of a chemical reaction, while not being consumed orundergoing a permanent chemical change itself.

[0031] The terms, “bidentate catalyst”, “tridentate catalyst”, and“tetradentate catalyst” refer to catalysts having, respectively, two,three, and four contact points with the substrate of the catalyst.

[0032] The term “complex” as used herein and in the claims means acoordination compound formed by the union of one or more electron-richand electron-poor molecules or atoms capable of independent existencewith one or more electronically poor molecules or atoms, each of whichis also capable of independent existence.

[0033] The term “alkyl” refers to the radical of saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In preferredembodiments, a straight chain or branched chain alkyl has 30 or fewercarbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀for branched chain), and more preferably 20 or fewer. Likewise,preferred cycloalkyls have from 3-10 carbon atoms in their ringstructure, and more preferably have 5, 6 or 7 carbons in the ringstructure.

[0034] Moreover, the term “alkyl” (or “lower alkyl”) as used throughoutthe specification and claims is intended to include both “unsubstitutedalkyls” and “substituted alkyls”, the latter of which refers to alkylmoieties having substituents replacing a hydrogen on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an ester, aformyl, or a ketone), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate,a phosphinate, an amino, an amido, an amidine, an imine, a cyano, anitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, asulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or anaromatic or heteroaromatic moiety. It will be understood by thoseskilled in the art that the moieties substituted on the hydrocarbonchain can themselves be substituted, if appropriate. For instance, thesubstituents of a substituted alkyl may include substituted andunsubstituted forms of amino, azido, imino, amido, phosphoryl (includingphosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido,sulfamoyl and sulfonate), and silyl groups, as well as ethers,alkylthios, carbonyls (including ketones, aldehydes, carboxylates, andesters), —CF₃, —CN and the like. Exemplary substituted alkyls aredescribed below. Cycloalkyls can be further substituted with alkyls,alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls,—CF₃, —CN, and the like.

[0035] The term “aralkyl”, as used herein, refers to an alkyl groupsubstituted with an aryl group (e.g., an aromatic or heteroaromaticgroup).

[0036] The terms “alkenyl” and “alkynyl” refer to unsaturated aliphaticgroups analogous in length and possible substitution to the alkylsdescribed above, but that contain at least one double or triple bondrespectively.

[0037] Unless the number of carbons is otherwise specified, “loweralkyl” as used herein means an alkyl group, as defined above, but havingfrom one to ten carbons, more preferably from one to six carbon atoms inits backbone structure. Likewise, “lower alkenyl” and “lower alkynyl”have similar chain lengths. Preferred alkyl groups are lower alkyls. Inpreferred embodiments, a substituent designated herein as alkyl is alower alkyl.

[0038] The term “aryl” as used herein includes 5-, 6-and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazineand pyrimidine, and the like. Those aryl groups having heteroatoms inthe ring structure may also be referred to as “aryl heterocycles” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromaticmoieties, —CF₃, —CN, or the like. The term “aryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings (the rings are “fusedrings”) wherein at least one of the rings is aromatic, e.g., the othercyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls.

[0039] The terms ortho, meta and para apply to 1,2-, 1,3-and1,4-disubstituted benzenes, respectively. For example, the names1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

[0040] The terms “heterocyclyl” or “heterocyclic group” refer to 3-to12-membered ring structures, more preferably 3-to 7-membered rings,whose ring structures include one to four heteroatoms. Heterocyclylgroups include, for example, thiophene, thianthrene, furan, pyran,isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole,pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine,pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, perimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactamssuch as azetidinones and pyrrolidinones, sultams, sultones, and thelike. The heterocyclic ring can be substituted at one or more positionswith such substituents as described above, as for example, halogen,alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulthydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or thelike.

[0041] The terms “polycyclyl” or “polycyclic group” refer to two or morerings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromaticmoiety, —CF₃, —CN, or the like.

[0042] The term “carbocycle”, as used herein, refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

[0043] The term “heteroatom” as used herein means an atom of any elementother than carbon or hydrogen. Preferred heteroatoms are nitrogen,oxygen, sulfur and phosphorous.

[0044] As used herein, the term “nitro” means —NO₂; the term “halogen”designates —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO₂-.

[0045] The terms “amine” and “amino” are art recognized and refer toboth unsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula:

[0046] wherein R₉, R₁₀ and R′₁₀ each independently represent a hydrogen,an alkyl, an alkenyl, —(CH₂)_(m)—R₈, or R₉ and R₁₀ taken together withthe N atom to which they are attached complete a heterocycle having from4 to 8 atoms in the ring structure; R₈ represents an aryl, a cycloalkyl,a cycloalkenyl, a heterocycle or a polycycle; and m is zero or aninteger in the range of 1 to 8. In preferred embodiments, only one of R₉or R₁₀ can be a carbonyl, e.g., R₉, R₁₀ and the nitrogen together do notform an imide. In even more preferred embodiments, R₉ and R₁₀ (andoptionally R′₁₀) each independently represent a hydrogen, an alkyl, analkenyl, or —(CH₂)_(m)—R₈. Thus, the term “alkylamine” as used hereinmeans an amine group, as defined above, having a substituted orunsubstituted alkyl attached thereto, i.e., at least one of R₉ and R₁₀is an alkyl group.

[0047] The term “acylamino” is art-recognized and refers to a moietythat can be represented by the general formula:

[0048] wherein R₉ is as defined above, and R′₁₁ represents a hydrogen,an alkyl, an alkenyl or —(CH₂)_(m)—R₈, where m and R₈ are as definedabove.

[0049] The term “amido” is art recognized as an amino-substitutedcarbonyl and includes a moiety that can be represented by the generalformula:

[0050] wherein R₉, R₁₀ are as defined above. Preferred embodiments ofthe amide will not include imides which may be unstable.

[0051] The term “alkylthio” refers to an alkyl group, as defined above,having a sulfur radical attached thereto. In preferred embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R_(8,) wherein m and R₈ are defined above.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

[0052] The term “carbonyl” is art recognized and includes such moietiesas can be represented by the general formula:

[0053] wherein X is a bond or represents an oxygen or a sulfur, and R₁₁represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R₈ or apharmaceutically acceptable salt, R′₁₁ represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R_(8,) where m and R₈ are as defined above.Where X is an oxygen and R₁₁ or R′₁₁ is not hydrogen, the formularepresents an “ester”. Where X is an oxygen, and R₁₁ is as definedabove, the moiety is referred to herein as a carboxyl group, andparticularly when R₁₁ is a hydrogen, the formula represents a“carboxylic acid”. Where X is an oxygen, and R′₁₁ is hydrogen, theformula represents a “formyl” group. In general, where the oxygen atomof the above formula is replaced by sulfur, the formula represents a“thiolcarbonyl” group. Where X is a sulfur and R₁₁ is not hydrogen, theformula represents a “thiolester.” Where X is a sulfur and R₁₁ ishydrogen, the formula represents a “thiolcarboxylic acid.” Where X is asulfur and R₁₁ ′ is hydrogen, the formula represents a “thiolformate.”On the other hand, where X is a bond, and R₁₁ is not hydrogen, the aboveformula represents a “ketone” group. Where X is a bond, and R₁₁ ishydrogen, the above formula represents an “aldehyde” group.

[0054] The terms “alkoxyl” or “alkoxy” as used herein refers to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R₈,where m and R₈ are described above.

[0055] The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognizedand refer to trifluoromethanesulfonyl, p-toluenesulfonyl,methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. Theterms triflate, tosylate, mesylate, and nonaflate are art-recognized andrefer to trifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

[0056] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

[0057] The term “sulfonate” is art recognized and includes a moiety thatcan be represented by the general formula:

[0058] in which R₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl, oraryl.

[0059] The term “sulfate” is art recognized and includes a moiety thatcan be represented by the general formula:

[0060] in which R₄₁ is as defined above.

[0061] The term “sulfonamido” is art recognized and includes a moietythat can be represented by the general formula:

[0062] in which R₉ and R′₁₁ are as defined above.

[0063] The term “sulfamoyl” is art-recognized and includes a moiety thatcan be represented by the general formula:

[0064] in which R₉ and R₁₀ are as defined above.

[0065] The term “sulfonyl”, as used herein, refers to a moiety that canbe represented by the general formula:

[0066] in which R₄₄ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0067] The term “sulfoxido” as used herein, refers to a moiety that canbe represented by the general formula:

[0068] in which R₄₄ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

[0069] A “phosphoryl” can in general be represented by the formula:

[0070] wherein Q₁ represented S or O, and R₄₆ represents hydrogen, alower alkyl or an aryl. When used to substitute, e.g., an alkyl, thephosphoryl group of the phosphorylalkyl can be represented by thegeneral formula:

[0071] wherein Q₁ represented S or O, and each R₄₆ independentlyrepresents hydrogen, a lower alkyl or an aryl, Q₂ represents O, S or N.When Q₁ is an S, the phosphoryl moiety is a “phosphorothioate”.

[0072] A “phosphoramidite” can be represented in the general formula:

[0073] wherein R₉ and R₁₀ are as defined above, and Q₂ represents O, Sor N.

[0074] A “phosphonamidite” can be represented in the general formula:

[0075] wherein R₉ and R₁₀ are as defined above, Q₂ represents O, S or N,and R₄₈ represents a lower alkyl or an aryl, Q₂ represents O, S or N.

[0076] A “selenoalkyl” refers to an alkyl group having a substitutedseleno group attached thereto. Exemplary “selenoethers” which may besubstituted on the alkyl are selected from one of —Se-alkyl,—Se-alkenyl, —Se-alkynyl, and —Se—(CH₂)_(m)—R₇, m and R₇ being definedabove.

[0077] Analogous substitutions can be made to alkenyl and alkynyl groupsto produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

[0078] The phrase “carboxyl-protecting group” as used herein refers tothose groups intended to protect a carboxylic acid group, such as theC-terminus of an amino acid or peptide or an acidic or hydroxyl azepinering substituent, against undesirable reactions during syntheticprocedures.

[0079] The term “amino-blocking group” is used herein as it isfrequently used in synthetic organic chemistry, to refer to a groupwhich will prevent an amino group from participating in a reactioncarried out on some other functional group, but which can be removedfrom the amine when desired.

[0080] The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

[0081] By the terms “amino acid residue” and “peptide residue” is meantan amino acid or peptide molecule without the —OH of its carboxyl group.In general the abbreviations used herein for designating the amino acidsand the protective groups are based on recommendations of the IUPAC-IUBCommission on Biochemical Nomenclature (see Biochemistry (1972)11:1726-1732). For instance Met, Ile, Leu, Ala and Gly represent“residues” of methionine, isoleucine, leucine, alanine and glycine,respectively. By the residue is meant a radical derived from thecorresponding α-amino acid by eliminating the OH portion of the carboxylgroup and the H portion of the ≢-amino group. The term “amino acid sidechain” is that part of an amino acid exclusive of the —CH(NH₂)COOHportion, as defined by K. D. Kopple, “Peptides and Amino Acids”, W. A.Benjamin Inc., New York and Amsterdam, 1966, pages 2 and 33; examples ofsuch side chains of the common amino acids are —CH₂CH₂SCH₃ (the sidechain of methionine), —CH₂(CH₃)—CH₂CH₃ (the side chain of isoleucine),—CH₂CH(CH₃)₂ (the side chain of leucine) or H—(the side chain ofglycine).

[0082] The term “amino acid” is intended to embrace all compounds,whether natural or synthetic, which include both an amino functionalityand an acid functionality, including amino acid analogs and derivatives.Also included in the term “amino acid” are amino acid mimetics such asβ-cyanoalanine, norleucine, 3-phosphoserine, homoserine,dihydroxyphenylalanine, 5-hydroxytryptophan, and the like.

[0083] In certain embodiments, the amino acids used in the applicationof this invention are those naturally occurring amino acids found inproteins, or the naturally occurring anabolic or catabolic products ofsuch amino acids which contain amino and carboxyl groups. Particularlysuitable amino acid side chains include side chains selected from thoseof the following amino acids: glycine, alanine, valine, cysteine,leucine, isoleucine, serine, threonine, methionine, glutamic acid,aspartic acid, glutamine, asparagine, lysine, arginine, proline,histidine, phenylalanine, tyrosine, and tryptophan, and those aminoacids and amino acid analogs which have been identified as constituentsof peptidylglycan bacterial cell walls.

[0084] The term “amino acid residue” further includes analogs,derivatives and congeners of any specific amino acid referred to herein,as well as C-terminal or N-terminal protected amino acid derivatives(e.g. modified with an N-terminal or C-terminal protecting group). Forexample, the present invention contemplates the use of amino acidanalogs wherein a side chain is lengthened or shortened while stillproviding a carboxyl, amino or other reactive precursor functional groupfor cyclization, as well as amino acid analogs having variant sidechains with appropriate functional groups). For instance, the subjectcompound can include an amino acid analog such as, for example,cyanoalanine, canavanine, djenkolic acid, norleucine, 3-phosphoserine,homoserine, dihydroxy-phenylalanine, 5-hydroxytryptophan,1-methylhistidine, 3-methylhistidine, diaminopimelic acid, ornithine, ordiaminobutyric acid. Other naturally occurring amino acid metabolites orprecursors having side chains which are suitable herein will berecognized by those skilled in the art and are included in the scope ofthe present invention.

[0085] Also included are the (D) and (L) stereoisomers of such aminoacids when the structure of the amino acid admits of stereoisomericforms. The configuration of the amino acids and amino acid residuesherein are designated by the appropriate symbols (D), (L) or (DL),furthermore when the configuration is not designated the amino acid orresidue can have the configuration (D), (L) or (DL). It will be notedthat the structure of some of the compounds of this invention includesasymmetric carbon atoms. It is to be understood accordingly that theisomers arising from such asymmetry are included within the scope ofthis invention. Such isomers can be obtained in substantially pure formby classical separation techniques and by sterically controlledsynthesis. For the purposes of this application, unless expressly notedto the contrary, a named amino acid shall be construed to include boththe (D) or (L) stereoisomers.

[0086] Certain compounds of the present invention may exist inparticular geometric or stereoisomeric forms. The present inventioncontemplates all such compounds, including cis- and trans-isomers, R-and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

[0087] If, for instance, a particular enantiomer of a compound of thepresent invention is desired, it may be prepared by asymmetricsynthesis, or by derivation with a chiral auxiliary, where the resultingdiastereomeric mixture is separated and the auxiliary group cleaved toprovide the pure desired enantiomers. Alternatively, where the moleculecontains a basic functional group, such as amino, or an acidicfunctional group, such as carboxyl, diastereomeric salts are formed withan appropriate optically-active acid or base, followed by resolution ofthe diastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

[0088] In the context of this invention, a “saccharide” refers to anymonosaccharide or oligosaccharide. A “monosaccharide” is a saccharidethat is not hydrolyzable into smaller saccharide units. Monosaccharidesinclude unsubstituted, non-hydrolyzable saccharides such as glucose, aswell as modified saccharides in which one or more hydroxyl groupscontain substitutions or have been replaced with hydrogen atoms (i.e.,deoxy, dideoxy and trideoxy saccharides). Azasugars are another exampleof a modified monosaccharide. Alternatively, a monosaccharide may bepresent within an oligosaccharide. “Oligosaccharides” are hydrolyzablesaccharides that contain two or more monosaccharides linked together ina linear or branched manner. Preferred oligosaccharides for use as turnelements in the subject invention are disaccharide and trisaccharide.

[0089] It will be understood that “substitution” or “substituted with”includes the implicit proviso that such substitution is in accordancewith permitted valence of the substituted atom and the substituent, andthat the substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

[0090] As used herein, the term “substituted” is contemplated to includeall permissible substituents of organic compounds. In a broad aspect,the permissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described hereinabove. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalencies of the heteroatoms. This invention is not intended to belimited in any manner by the permissible substituents of organiccompounds.

[0091] For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87, insidecover. Also for purposes of this invention, the term “hydrocarbon” iscontemplated to include all permissible compounds having at least onehydrogen and one carbon atom. In a broad aspect, the permissiblehydrocarbons include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic organic compoundswhich can be substituted or unsubstituted.

[0092] The term “immobilized”, used with respect to a species, refers toa condition in which the species is attached to a surface with anattractive force stronger than attractive forces that are present in theintended environment of use of the surface, and that act on the species.For example, a chelating agent immobilized at a surface, the surfacebeing used to capture a biological molecule from a fluid medium, isattracted to the surface with a force stronger than forces acting on thechelating agent in the fluid medium, for example solvating and turbulentforces.

[0093] The term “solid support” refers to a material which is aninsoluble matrix, and may (optionally) have a rigid or semi-rigidsurface. Such materials will preferably take the form of small beads,pellets, disks, chips, dishes, multi-well plates, wafers or the like,although other forms may be used. In some embodiments, at least onesurface of the substrate will be substantially flat. The term “surface”refers to any generally two-dimensional structure on a solid substrateand may have steps, ridges, kinks, terraces, and the like withoutceasing to be a surface.

[0094] The term “polymeric support”, as used herein, refers to a solubleor insoluble polymer to which an amino acid or other chemical moiety canbe covalently bonded by reaction with a functional group of thepolymeric support. Many suitable polymeric supports are known, andinclude soluble polymers such as polyethylene glycols or polyvinylalcohols, as well as insoluble polymers such as polystyrene resins. Asuitable polymeric support includes functional groups such as thosedescribed below. A polymeric support is termed “soluble” if a polymer,or a polymer-supported compound, is soluble under the conditionsemployed. However, in general, a soluble polymer can be renderedinsoluble under defined conditions. Accordingly, a polymeric support canbe soluble under certain conditions and insoluble under otherconditions.

[0095] The term “functional group of a polymeric support”, as usedherein, refers to a chemical moiety of a polymeric support that canreact with an chemical moiety to form a polymer-supported amino ester.Exemplary functional groups of a polymeric support include hydroxyl andsulfhydryl, and the like. Preferred functional groups of a polymericsupport will form polymer-supported amino esters that are covalentlybound to the polymeric support under mild conditions that do notadversely affect the polymer or the amino ester, and that aresufficiently stable to be isolated.

[0096] The term “synthetic” refers to production by in vitro chemical orenzymatic synthesis.

[0097] The phrases “individually selective manner” and “individuallyselective binding”, with respect to a recognition event involving apotential catalyst, refers to the recognition event which is specificfor, and dependent on, the molecular identity of the potential catalyst.

[0098] The term “meso compound” is recognized in the art and means achemical compound which has at least two chiral centers but is achiraldue to an internal plane or point of symmetry.

[0099] The term “chiral” refers to molecules which have the property ofnon- superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. A “prochiral molecule” is a molecule which has thepotential to be converted to a chiral molecule in a particular process.

[0100] The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space. In particular, “enantiomers” refer to twostereoisomers of a compound which are non-superimposable mirror imagesof one another. “Diastereomers”, on the other hand, refers tostereoisomers with two or more centers of asymmetry and whose moleculesare not mirror images of one another.

[0101] Furthermore, a “stereoselective process” is one which produces aparticular stereoisomer of a reaction product in preference to otherpossible stereoisomers of that product. An “enantioselective process” isone which favors production of one of the two possible enantiomers of areaction product.

[0102] The term “regioisomers” refers to compounds which have the samemolecular formula but differ in the connectivity of the atoms.Accordingly, a “regioselective process” is one which favors theproduction of a particular regioisomer over others, e.g., the reactionproduces a statistically significant increase in the yield of a certainregioisomer.

[0103] The term “epimers” refers to molecules, e.g., saccharides, withidentical chemical constitution and containing more than onestereocenter, but which differ in configuration at onlu one of thesestereocenters.

[0104] The term “anomers” refers to saccharides that differ inconfiguration only at the anomeric carbon.

[0105] III. Description of Catalyst Libraries.

[0106] In general, the invention contemplates the use of modularcomponents, also referred to herein as “subunits”, to construct alibrary of potential catalysts, e.g., that catalyzeindustrially-relevant organic or inorganic transformations. The modularcomponents are preferably molecular units which can be combined, such asthrough simultaneous or sequential coupling steps, to construct morecomplex compounds that are capable of stabilizing the transition stateof a given transformation. Such modular components can be associatednon-covalently, but are preferably linked covalently to one another,e.g. through amide, ester, thioester, carbamate, carbonate, disulfide,hydrazido, phosphodiester linkages and the like. Conveniently, modularcomponents can be selected to facilitate catalyst assembly, e.g.,modular components are selected so that coupling of the individualcomponents may be performed according to efficient, reliable techniquessuch as amino acid coupling, ester bond formation, and the like.

[0107] In one embodiment, illustrated in FIG. 5, the modular componentsof the subject method include at least two different classes ofmonomeric chemical moieties. The first group of monomers (or subunits)are referred to herein as “Catalyst Functional Groups” or “CFGs”, andinclude compounds comprising one or more functional groups capable ofbinding and/or covalently modifying a substrate. The second group ofmonomers are the “Turn Element Groups” or “TEGs”. These units serve asbranching points for disposing two or more CFGs in space. In general,the turn elements will be compounds with defined relative and absolutestereochemistry, and are introduced with the notion that suchconformational restriction can encourage the formation of a potentialbinding site in which one or more functionalities of the CFGs interactwith a substrate. That is, the turn element arranges the functionalgroups of the attached CFGs in space with potential conformations thatpermit the resulting molecule to interact with and catalyze thetransformation of the substrate(s).

[0108] A third, though optional group of monomeric subunits are the“spacers elements” (not shown in FIG. 5). These compounds are notintended to contain any functional groups which may interact to anygreat degree with a substrate, rather they are incorporated in thepotential catalysts merely to alter the spatial arrangement offunctional groups provided by the CFGs. That is, the spacer elementsprovide greater steric and/or stereochemical diversity in a potentialcatalyst library.

[0109] The libraries can also include “end cap” elements and linkers,which may or may not effect the ability of functional groups of the CFGsto provide a catalytic site. In certain embodiments, the selection ofend cap elements can be motivated, at least in part, by such factors asan elements ability to protect CFG substituents, to enhance solubilityunder certain conditions, and/or to provide certain steric environmentsaround a potential catalytic site formed by CFGs.

[0110] In one embodiment, illustrated below in Scheme 1, the library iscomposed of potential catalysts comprising five elements: 1) a solidsupport; 2) a first linker domain (Linker₁); 3) an amino acid; 4) asecond linker domain (Linker₂); and 5) a catalytic moiety. The solidsupport is selected from available supports such that detachment of thepotential catalyst from the solid support is possible under mildreaction conditions. Both of the linkers may be selected from the set ofdifunctional compounds, either with or without sidechains and/orstereocenters, that allow for attachment to the both the solid supportand the amino acid, or the amino acid and the catalytic moiety,respectively, via well-characterized linking functional groups.

[0111] As illustrated by FIG. 5 and Scheme 1, a library of potentialcatalysts is generated by the combinatorial coupling of one or morelinkers and/or turn elements with one or more catalytic moieties (CFGs).Diversity can be generated in the library in any of a number of ways.The potential catalyst library can be generated based upon a variegatedpopulation of CFGs. For instance, the CFGs can introduce variation intothe library due to the presence in these compounds of differentfunctional groups, as well as differences in the locations (positions ofattachment) and dispositions of these functional groups in the CFGstructure, e.g., differences arising from chemical and steric featuresand/or stereochemistry of the CFG. To illustrate, where the CFGs of thepotential catalysts of the library include amino acids, the library canbe generated with different amino acids, e.g., aspartic acid, glutamicacid, histidine, cysteine, methionine or tyrosine, etc., as well usingdifferent isomers of a given amino acid, e.g., L and D isomers.

[0112] Heterogeneity in the potential catalyst library can also beintroduced by the use of variegated populations of turn elements. Asdetailed below, the turn elements used in the combinatorial synthesiswhich constitute the generation of the library can be compounds ofdifferent chemical make-up and/or of different stereochemistries. Forinstance, a library of potential catalysts can be generated from amixture of different cyclic diols and diamines as turn elements.

[0113] The stereochemistry of the turn elements can also be used tovariegate the potential catalyst library, such as by the inclusion ofdifferent stereoisomers of the same compound, e.g., resulting indiastereomeric, enantiomeric and/or regioisomeric diversity in thelibrary.

[0114] Yet another means for introducing diversity into the potentialcatalyst library is through the use of spacer elements. These elementsof the library provide variability in the library with respect torelative distance and/or orientation of the functional groups of theCFGs. For example, a given spacer element may be alkyl chains of varyinglengths. It will be understood that the role of an individual spacerelement can be effectively duplicated by inclusion of the group in a CFGor turn element.

[0115] The number of diversomers at any given position in the potentialcatalyst library is the sum of different chemical moieties and/orstereoisomers which can occur at that position. Thus, in an illustrativeembodiment where the potential catalysts of a given library have oneturn element position, the members of the library can be represented bythe general formula T(—R)n where T represents a turn element, n is thenumber of substituted branch points on the turn element (e.g., aninteger greater than or equal to 2) and R represents, independently foreach of its n occurrences, a sidechain comprising one or more CFGs. Thenumber of different potential catalysts which can be provided in such alibrary is given by the formula TE×[Z₁×Z₂×. . . Z_(m)]₁×[Z₁×Z₂×. . .Z_(m)]₂×. . . [Z₁×Z₂×. . . Z_(m)]_(n), where TE is the number of turnelement groups, and each Z is the number of CFGs (or other diversomer)at each of m combinatorial positions in each of the n ligand sidechainsbranching from the turn element. The number of diversomers at any givenposition in the library, be it a turn element or in a moiety provided ina sidechain of interest, is the sum of different chemical moietiesand/or stereoisomers which can occur at that position. In preferredembodiments, the potential catalyst library includes at least 100different molecular species, more preferably at least 10³, 10⁴ or 10⁵different species of potential catalyst, though libraries within therange of conventional combinatorial synthesis techniques areanticipated, e.g., exceeding 10³ distinct members.

[0116] a). Catalyst Functional Groups

[0117] The role of the CFG moieties is to provide functional moieties inthe catalyst structure that can bind to and/or covalently modify asubstrate or substrates. As set out above, such groups can provide in acatalyst the ability to selectively bind a substrate, stabilize atransition state, and/or participate as a covalent catalyst. That is,the combinatorial synthesis of catalyst libraries from CFG monomers isintended to provide poly-functionalized compounds. In general, thecatalysts of the present invention will include organic electron donoror acceptor moieties. Accordingly, in a preferred embodiment, thesubject libraries are generated with CFGs including one or morefunctional groups having an electron pair donor (Lewis base) which canact as a nucleophile, and/or an electron pair acceptor (Lewis acid)which can acts as an electrophile, as appropriate, for the reaction tobe catalyzed. In the case of the former, the functional group willpreferably be a strongly acidic group, e.g., with a pKa less than about7, and more preferably less than 5, which can produce a conjugate basethat, under the reaction conditions, is a strong enough Lewis base todonate an electron pair. In the case of the latter, the functional groupwill preferably be a hydrogen-bond donor, an atom with a vacant orbital,or an atom capable exchanging one bound Lewis base for another.

[0118] As set out above, the term “Lewis base” refers to any chemicalspecies which is an electron pair donor. The types of Lewis basicfunctional groups useful in the subject catalysts are too numerous tocategorize, though in preferred embodiments such compounds will includebases which bear atoms from Periodic Groups 15 and 16.

[0119] Lewis bases from Group 15 contain nitrogen, phosphorous, arsenic,antimony or bismuth atoms as electron pair donors. Preferable Lewisbases from Group 15 contain nitrogen, phosphorous, and antimony, andmore preferably, nitrogen or phosphorous.

[0120] Lewis bases from Group 16 contain oxygen, sulfur, or seleniumatoms as electron pair donors. Preferable Lewis bases from Group 16contain oxygen or sulfur.

[0121] Exemplary Lewis basic moieties which can be used in the CFGsinclude amines (primary, secondary, and tertiary) and aromatic amines,amino groups, amido groups, nitro groups, nitroso groups, aminoalcohols, nitrites, imino groups, isonitriles, cyanates, isocynates,phosphates, phosphonates, phosphites, (substituted) phosphines,phosphine oxides, phosphorothioates, phosphoramidates, phosphonamidites,hydroxyls, carbonyls (e.g., carboxyl, ester and formyl groups),aldehydes, ketones, ethers, carbamoyl groups, thiols, sulfides,thiocarbonyls (e.g., thiolcarboxyl, thiolester and thiolformyl groups),thioethers, mercaptans, sulfonic acids, sulfoxides, sulfates,sulfonates, sulfones, sulfonamides, sulfamoyls and sulfinyls.

[0122] Illustrative of suitable CFGs are those organic compoundscontaining at least one Lewis basic nitrogen, sulfur, phosphorous oroxygen atom or a combination of such nitrogen, sulfur, phosphorous andoxygen atoms. The carbon atoms of the CFGs can be part of an aliphatic,cycloaliphatic or aromatic moiety. Typically, the CFG will contain atleast 2 carbon atoms, though generally no more than 40 carbon atoms. Inaddition to the organic Lewis base(s), the CFG may also contain otheratoms and/or groups as substituents, such as alkyl, aryl and halogensubstituents. Catalytic moieties useful in generating potentialcatalysts in the subject method include linear and branched functionalolefinic compounds having at least one functional terminal reactivegroup which can act as a Lewis base. Examples of the Lewis base are:amines, particularly alkylamines and arylamines, including methylamine,diphenylamine, trimethylamine, triethylamine, N,N-dimethylaniline,methyldiphenylaniline, pyridine, aniline, morpholine,N-methylmorpholine, pyrrolidine, N-methyilpyrrolidine, piperidine,N-methylpiperidine, cyclohexylamine, n-butylamine, dimethyloxazoline,imidazole, N-methylimidazole, N,N-dimethylethanolamine,N,N-diethylethanolimine, N,N-ipropylethanolamine,N,N-dibutylethanolamine, N,N-dimethylisopropanolamine,N,N-diethylisopropanolamine, N,N-dipropylisopropanolamine,N,N-dibutylisopropanolamine, N-methyldiethanolamine,N-ethyldiethanolamine, N-propyldiethanolamine, N-butyldiethanolamine,N-methyldiisopropanolamine, N-ethyldiisopropanolamine,N-propyldiisopropanolamine, N-butyldiisopropanolamine, triethylamine,triisopropanolamine, tri-s-butanolamine and the like; amides, such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,hexamethylphosphoric acid triamide and the like; sulfoxide compounds,such as dimethylsulfoxide and the like; ethers such as dimethyl ether,diethyl ether, tetrahydrofuran, dioxane and the like; thioethers such asdimethylsulfide, diethyl thioether, tetrahydrothiophene and the like;esters of phosphoric acid, such as trimethyl phosphate,triethylphosphate, tributyl phosphate and the like; esters of boricacid, such as trimethyl borate and the like; esters of carboxylic acids,such as ethyl acetate, butyl acetate, ethyl benzoate and the like;esters of carbonic acid, such as ethylene carbonate and the like;phosphines, including di- and trialkylphosphines, such astributylphosphine, triethylphosphine, triphenylphosphine,diphenylphosphine and the like; and monohydroxylic andpolyhydroxylicalcohols of from 1 to 30 carbon atoms such as methylalcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butylalcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol,isopentyl alcohol, 2-methyl-1-butyl alcohol, 2-methyl-2-butyl alcohol,n-hexyl alcohol, n-heptyl alcohol, n-octyl alcohol, isooctyl alcohol,2-ethylhexyl alcohol, n-nonyl alcohol, n-decyl alcohol, 1,5-pentanediol,1,6-hexanediol, allyl alcohol, crotyl alcohol, 3-hexene-1-ol,citronellol, cyclopentanol, cyclohexanol, salicyl alcohol, benzylalcohol, phenethyl alcohol, cinnamyl alcohol, and the like.

[0123] As a further illustration, exemplary CFGs include bifunctionalcompounds such as amino acids, hydroxy acids, hydroxy thiols, mercaptoamines, and the like. The term “amino acid” is intended to embrace allcompounds, whether natural or synthetic, which include both an aminofunctionality and an acid functionality, including amino acid analogsand derivatives. Also included in the term “amino acid” are amino acidmimetics such as β-cyanoalanine, norleucine, 3-phosphoserine,homoserine, dihydroxyphenylalanine, 5-hydroxytryptophan, and the like.Such CFGs can include any and/or all stereoisomers when the modularcomponent admits of such isomers.

[0124] Other exemplary modular components include nucleic acids andnucleic acid analogs and derivatives, diacids, diamines, and the like.In certain embodiments, modular components of different types can becombined to form a library of potential catalysts. For example, a diacidmodular component can react with a diamine modular component to producean amide bond.

[0125] In certain preferred embodiments, if a variegated potentialcatalyst library comprises amino acids, at least one modular componentwill be a non-naturally-occurring amino acid. The process of selectingsuitable non-natural amino acids for use in the present invention willparallel the selection of natural amino acids in the invention. Forexample, preferred embodiments of the natural amino acids identifiedabove include nitrogen or sulfur atoms, e.g., histidine and cysteine.Similarly, preferred non-natural amino acids will also incorporate anitrogen and/or a sulfur center.

[0126] If desired, one functionality can be selectively protected orblocked to permit reaction of an unblocked functional group. Thus, forexample, amino acids, nucleotides, and saccharides can be blocked anddeblocked according to known procedures.

[0127] b). Turn Elements

[0128] A salient feature of the turn elements of the subject catalystsis that they can provide spatial preorganization of the CFGs intoconformations which can be complementary to the geometries of asubstrate or substrates, a transition state, intermediate, and/or aproduct of a desired reaction. The combinatorial approach allows theoptimization of catalytic rate enhancements and/or specificities byaccessing large numbers of spatial arrangements of CFGs.

[0129] In addition to availability, reactivity and stability, a criteriain the selection of turn elements for generating the potential catalystlibrary is the “rigidity” of the molecule. For purposes of the inventiondescribed herein, the term “rigid” refers to the physical state ofmolecular structures having fewer intramolecular rotational degrees offreedom than a simple linear chain. The choice of turn elementspreferably favors groups with limited degrees of freedoms, thoughexamples of linear elements are provided below as well. In preferredembodiments, an individual turn element has a reduced number ofinternally rotatable bonds, e.g., relative to a straight chain alkyl.

[0130] The stereochemical constraints of a cyclic element can serve toorient and predispose the CFGs of its substituents and thereby impartmaximal interaction with the, e.g. transition state of a transformation.In this manner, a turn element can be selected with optimizedcomplementarity and pre-organization in mind, e.g., for reducing theentropic cost of recognition of the transition state.

[0131] The ability to utilize stereochemical diversity in the turnelement(s) further illustrates this point. Beginning with ameso-epoxide, enantioselective ring opening can provide enantiomericallyenriched turn elements which can be further derivatized with, e.g.,stereochemically defined CFGs to yield libraries of diastereomericallyvariegated compounds.

[0132] To further elaborate, in one representative embodiment, Tentagel,a polystyrene-polyethylene glycol copolymer resin (Rappe Polymere,Tubingen, Germany) having a cleavable linking arm is cleaved by strongacidic conditions (such as trifluoroacetic acid), is esterified with4-nitrophenyl chloroformate. The resin is then reacted withtetrahydro-1aH-cyclopenta[b]oxiren-3-ylmethanol to yield theepoxide-derived resin.

[0133] The epoxide is then enantioselectively opened with trimethylsilylazide (TMSN₃) in the presence of a chiral salen catalyst[1,2,-bis(3,5-di-tert-butylsalicylide-amino)cyclohexane:Cr, e.g., seeU.S. Pat, No. 5,665,890] to yield, in the illustrate reaction, theenantiomerically enriched 3-azido4-trimethylsilyloxy-cyclopentyl derivedpolymer. This serves as a useful

[0134] intermediate in the generation of the subject libraries, and thetechnique can be generally applied to many other epoxides.

[0135] In preferred embodiments, the turn element is a ring moiety,e.g., a carbocyclic or heterocyclic moiety which may be monocyclic orpolycyclic, aromatic or non-aromatic. Exemplary turn elements of thistype include, but are not limited to, acridarsine, acridine, anthracene, arsindole, arsinoline, azepane, benzene, carbazole, carboline,chromene, cinnoline, furan, furazan, hexahydropyridazine,hexahydropyrimidine, imidazole, indane, indazole, indole, indolizine,isoarsindole, isobenzofuran, isochromene, isoindole, isophosphindole,isophosphinoline, isoquinoline, isorasinoline, isothiazole, isoxazole,morpholine, naphthalene, naphthyridine, oxazole, oxolane, perimidine,phenanthrene, phenanthridine, phenanthroline, phenarsazine, phenazine,phenomercurazine, phenomercurin, phenophosphazine, phenoselenazine,phenotellurazine, phenothiarsine, phenoxantimonin, phenoxaphosphine,phenoxarsine, phenoxaselenin, phenoxatellurin, phenothiazine,phenoxathiin, phenoxazine, phosphanthene, phosphindole, phosphinoline,phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrolidine, pyrrolizine,quinazoline, quinoline, quinolizine, quinoxaline (such as pyrrole),selenanthrene, selenophene, tellurophene, tetrahydrofuran,tetrahydrothiophene, thianthrene, thiazole, thiolane, thiophene orxanthene.

[0136] Thus, in one embodiment the potential catalysts of the librarycan be represented by the general formula:

[0137] wherein

[0138] A represents a carbocycle or heterocycle which can be monocyclicor polycyclic, aromatic or non-aromatic;

[0139] R₁ and R₂ each represent, independently for each occurrence in apotential catalyst of a library, an CFG including a moiety selected fromthe group consisting of amines (primary, secondary, and tertiary andaromatic amines), amino groups, amido groups, nitro groups, nitrosogroups, amino alcohols, nitrites, imino groups, phosphates,phosphonates, phosphites, (substituted) phosphines, phosphine oxides,phosphorothioates, phosphoramidates, phosphonamidites, hydroxyls,carbonyls (e.g., carboxyl, ester and formyl groups), aldehydes, ketones,ethers, carbamoyl groups, thiols, sulfides, thiocarbonyls (e.g.,thiolcarboxyl, thiolester and thiolformyl groups), thioethers,mercaptans, sulfonic acids, sulfates, sulfonates, sulfonones,sulfonamides, sulfamoyls and sulfinyls, or alkyl, alkenyl or alkynylgroups (preferably in the range of C₁-C₃₀) substituted therewith; and

[0140] R₃ is absent or represents one or more further CFG substitutionsto the ring A, each occurrence of which independently includes a moietyselected from the group consisting of amines (primary, secondary, andtertiary and aromatic amines), amino groups, amido groups, nitro groups,nitroso groups, amino alcohols, nitrites, imino groups, phosphates,phosphonates, phosphites, (substituted) phosphines, phosphine oxides,phosphorothioates, phosphoramidates, phosphonamidites, hydroxyls,carbonyls (e.g., carboxyl, ester and formyl groups), aldehydes, ketones,ethers, carbamoyl groups, thiols, sulfides, thiocarbonyls (e.g.,thiolcarboxyl, thiolester and thiolformyl groups), thioethers,mercaptans, sulfonic acids, sulfates, sulfonates, sulfonones,sulfonamides, sulfamoyls and sulfinyls, or alkyl, alkenyl, alkynyl oraryl groups (preferably in the range of C₁-C₃₀) substituted therewith.

[0141] Another source of elements for the subject method are theconformationally constrained mimetics used to generate peptidomimetics,for example, the benzodiazepines (see, e.g., James et al. (1993) Science260:1937), substituted lactam rings (Garvey et al. in Peptides:Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden,Netherlands, 1988, p123) and phenoxathin ring systems (Kemp et al.(1988) Tetrahedron Lett. 29:4931; Kemp et al. (1988) Tetrahedron Lett.29:4935). Thus, many of the conformational motifs used in thepeptidomimetic art, such as β-turns, are used to advantage in thepresent potential catalyst design protocol.

[0142] To illustrate, an element of the subject method can be either anexternal or internal β-turn mimetic. External β-turn mimetics were thefirst to be produced. Friedinger et al. (1980) Science 210:656-658,discloses a conformationally constrained nonpeptide β-turn mimeticmonocyclic lactam. In preferred embodiments, the element is asubstituted lactam, e.g., either a monocyclic or a polycyclic lactam. Asused herein, a “lactam” includes any organic ring having an amidelinkage internal to the ring, as for example β-carbolines containingγ-or δ-lactam ring.

[0143] In still another embodiment, an element of the potentialcatalysts may be a polycyclic moiety, e.g., having two or more ringswith two or more common (bridgehead) ring atoms, e.g., so that there arethree or more different paths (bridging substituents) between thebridgehead atoms.

[0144] In certain instances, an element of the potential catalysts willbe a polycyclic alkane, or bridged carbocycle, and may preferably be abicyclic alkane. The generic name for bicyclic alkanes isbicyclo[x.y.z]alkane, where x, y and z are the numbers of interveningcarbon atoms on the three paths between the two bridgehead carbons.Similar nomenclature is used for bridged heterocycles. Exemplarybicyclic alkanes for use in the present invention include such compoundsas: 2-methylbicyclo[2.1.0]pentane, bicyclo[2.1.1 ]hexane,1,4-dimethylbicyclo[2.2.0]hexane, bicyclo[2.2.1]heptane (norbornane),7,7-dimethylbicyclo[2.2.1 ]heptane,endo-2-isopropyl-7,7-dimethylbicyclo[2.2.1 ]heptane,trans-bicyclo[4.4.0]decan-3-one, bicyclo[2.2.2]octane,1,4-diisopropylbicyclo[2.2.2]octane,(2S,3S)-2-ethyl-3-methyl-bicyclo[2.2.2]octane, bicyclo[3.1.0]hexane,2,6,6-trimethylbicyclo[3.1.1]heptane, bicyclo-[3.2.0]heptane,bicyclo[3.2.2]nonane, bicyclo[3.3.0]octane,1,2-dimethylbicyclo-[3.3.0]octane, bicyclo[3.3.3]undecane,bicyclo[4.1.0]heptane,(1S,2R,4S,6R)-4-ethyl-2-isopropylbicyclo[4.1.0]heptane,cis-bicyclo[4.2.1]nonane, 1,9-dimethylbicyclo[4.2.1]nonane,trans-1,6-dibromobicyclo[4.3.0]nonane,1-methyl-8-propylbicyclo-[4.3.0]nonane, bicyclo[4.3.2]undecane,cis-bicyclo[4.4.0]decane (cis-decalin), trans-bicyclo[4.4.0]decane(trans-decalin), and trans-bicyclo[4.4.0]decan-3-one,

[0145] In other instances, the polycycle used can be a bridgedheterocycle. The bridging substituent can be, for example, an azimino(—N=N—HN—), an azo (—N—N—), a biimino (—NH—NH—), an epidioxy (—O—O—), anepidithio (—S—S—), an epithio (—S—), an epithioximino (—S—O—NH—), anepoxy (—O—), an epoxyimino (—O—NH—), an epoxynitrilo (—O—N=), anepoxythio (—O—S—), an epoxythioxy (—O—S—O—), a furano (—C₄H₂O—), animino (—NH—), or a nitrilo (—N=) moiety. Exemplary bridged heterocyclesinclude 7-azabicyclo-[2.2.1]heptane, and3,6,8-trioxabicyclo[3.2.2]nonane, 2,6-dioxabicyclo[3.2.1]oct-7-y1, andsubstituted forms thereof.

[0146] Preferred bicyclic moieties are those in which each bridgingsubstituent includes at least one atom between each bridging atom, e.g.,x, y and z are each integers equal to or greater than 1.

[0147] In similar fashion, other cyclic elements include polycycleshaving three or more bridging atoms and three or more rings, e.g., suchas the so-called polycyclic cage compounds. For instance, the turnelement can be derived from adamantane, diamantane, cubane,quadricyclene (tetracyclo[2.2.1.0(^(2,6)).0^((3,5))]heptane), to namebut a few. Compounds containing adamantane subunits, for example, havebeen of interest to chemists due to the rigid structure and well-definedsubstitution chemistry of the tricyclic compound. This feature of theadamantane molecule can be exploited to generate the subject potentialcatalysts. Moreover, numerous synthetic schemes have been derived forsubstituting the adamantane rings. See, for example, U.S. Pat. No.3,388,164 and U.S. Pat. No. 3,391,142 (synthesis of aminoadamantane);Molle et al. (1982) J Org Chem 47:4120 (carbocation chemistry of theadamantane system), and U.S. Pat. No. 5,599,998 (substitution ofhalo-adamantanes).

[0148] In another embodiment, an element of the potential catalysts is asaccharide, preferably a mono-, di- or trisaccharide. In preferredembodiments, the element is derived from a pentose or hexose sugar orazasugar. Where the saccharide is attached to the solid support, it canbe attached glycosidically, retaining the anomeric carbon of the sugar.In other embodiments, the saccharides can be subjected to reductiveamination in the presence of a solid support bearing a terminal aminefunctionality, thereby converting the reducing sugar to an aminoalditol.In an illustrative embodiment of the latter, a pentose sugar having aparticular stereoconfiguration about each chiral center is coupled toamino groups of polymer (such as amino ethylated polyacrylamide). Forinstance, the reducing end of the sugar can be attached to anamino-functionalized surface by reductive amination in the presence ofsodium cyanoborohydride.

[0149] The resulting 1,2,3,4-pentanetetraol provides hydroxyl groups atseveral asymmetric carbons which are available for furtherderivatization. Because a myriad of cheap, enatiomerically-pure sugarsare readily available, such sugars represent an excellent source for achiral pool of library elements, e.g., which introduce stereochemicaldiversity.

[0150] Specific examples of monosaccharides useful in the subjectinvention include hexoses such as glucose, mannose, galactose,glucosamine, mannosamine and galactosamine; and pentoses such asarabinose, xylose and ribose. Specific examples of oligosaccharides, onthe other hand, include disaccharides such as maltose, lactose,trehalose, cellobiose, isomaltose, gentiobiose, melibiose,laminaribiose, chitobiose, xylobiose, mannobiose and sophorose.

[0151] In yet another embodiment, an element of the libraries is anazasugar or a phosphanyl sugar, or a derivative thereof. Azasugarsinclude a class of saccharides in which the ring oxygen is replaced by anitrogen, or in which a ring carbon is replaced with an amino group. Asix-membered ring azasugar can be referred to as an azapyranose or apolyhydroxylated piperidine compound. A five-membered ring azasugar canbe referred to as an azafuranose or a polyhydroxylated pyrrolidine. Anazasugar can also be named as an aza derivative of an otherwisesystematically or trivially named pyranose or furanose monosaccharide.Exemplary azasugars which can be used as turn elements may be derivedfrom piperidines (azapyranoses) or from pyrrolidines (azafuranoses).Likewise, phosphanyl sugars include sugars in which a ring postion isreplaced with a phosphanyl group.

[0152] An exemplary use of an azasugar element is illustrated below. Anazapyranose, such as the (2S,3S,4S,SR)-azapyranose shown, can be coupledby well-known protocols to an amine-containing support using ahomobifunctional element such as malonic acid (n=1), succinic acid (n=2)or the like as a tether to the support.

[0153] Naturally occurring azasugars can be used as elements. Exemplaryazasugars of this type include 1-deoxynojirimycin(1,5-dideoxy-1,5-imino-D-glucitol), 1-deoxymannojirimycin(1,5-dideoxy-1,5-imino-D-mannitol), and castanospermine(1,6,7,8-tetrahydroxy-octahydroindolizine). 1-Deoxynojirimycin isisolated from plants of the genus Morus (Yagi et al., Nippon NogeiKagaku Kaishi 1976, 50:5751; Vasella et al., Helv. Chim. Acta, 198265:1134) and from strains of Bacillus (Daigo et al., Chem. Pharm. Bull.1986, 34:2243). 1-Deoxymannojirimycin is isolated from the legumeLonchocarpus (Fellows et al., J. C. S. Chem. Comm. 1979, 977).Castanospermine is a plant alkaloid isolated from seeds of an Australianchestnut tree, Castanospermum australe (Saul et al. Arch. Biochem.Biophys. 1983, 221:593].

[0154] Both synthetic and semi-synthetic routes have also been used inthe syntheses of azasugars and can be readily adapted for generatingelements in the subject libraries. For instance, synthetic routes toazasugars have commonly entailed processes such as azidedisplacement/reduction and N-alkylative cyclization with extensiveprotecting-group manipulation. See, for example, Paulsen et al. (1967)Chem. Ber 100:802; Inouye et al. (1968) Tetrahedron 23:2125; Saeki etal. (1968) Chem. Pharm. Bull. 11:2477; Kinast et al. (1981) Angew. Chem.Int. Ed. Engl. 20:805; U.S. Pat. No. 4,266,025; Vasella et al. (1982)Helv. Chim. Acta 65:1134; U.S. Pat. No. 4,611,058; Bernotas et al.(1985) Tetrahedron Lett. 26:1123; Setoi et al. (1986) Chem. Pharm. Bull.34:2642; Broxterman et al. (1987) Rec. Trav. Chim. Pays-Bas 106:571;Fleet et al. (1987) Tetrahedron 43:979; lida et al. (1987) J. Org. Chem.52:3337; Ziegler et al. (1988) Angew Chem. Int. Ed. Engl. 27:716;Schmidt et al. (1989) Liebigs Ann. Chem. 423; Chida et al. (1989) J.Chem. Soc., Chem. Commun. 1230; Beaupere et al. (1989) Carbohydr. Res.191:163; von der Osten et al. (1989) J. Am. Chem. Soc. 111:3924; Ikota,N. (1989) Heterocycles 22:1469; Tsuda et al. (1989) Chem. Pharm Bull37:2673; Fleet et al. (1990) Tetrahedron Lett. 31:490; Anzeveno et al.(1990) Tetrahedron Lett. 31:2085; and Dax et al. (1990) Carbohydr. Chem.9:479.

[0155] Natural sugars have been used as starting materials for theproduction of azasugars, though multiple protection and deprotectionsteps are required. For example, glucose can be used in the synthesis of1-deoxynojirimycin and 1-deoxymannojirimycin (Bernotas et al., 1985,supra; and Chen et al., (1990) Tetrahedron Lett. 31:2229).

[0156] TRIS and related compounds can also be ideal bi-functionalmolecules for use in the subject libraries. To illustrate:

[0157] c. End Caps

[0158] Another potential component in the synthesis of the subjectcatalyst libraries are so-called “end cap” units. In general, thesecomponents can serve several different purposes. They can, for example,be used as protecting groups for the ends of each string of CFG subunitssubstituted on a turn element. However, the end caps can also play arole in the catalytic activity of a potential catalyst, e.g.contributing to both affinity and specificity. For instance, the end capgroups can themselves include Lewis acidic and/or basic moieties whichcontribute to catalytic activity, and in this regard they may also beconsidered CFG groups. The selection of the end cap can also providesteric diversity in a library. Likewise, by the use ofelectron-withdrawing and/or electron-donating groups on the end cap, theLewis basicity of neighboring CFG units may be influenced. The selectionof the end cap can also be used to affect solubility of the potentialcatalyst.

[0159] Examples of end cap groups for carboxyl groups include, forexample, benzyl ester, cyclohexyl ester, 4-nitrobenzyl ester, t-butylester, 4-pyridylmethyl ester, and the like.

[0160] Examples of suitable end cap groups for amine include acylprotecting groups such as, to illustrate, formyl, dansyl, acetyl,benzoyl, trifluoroacetyl, succinyl, methoxysuccinyl, benzyl andsubstituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, andtriphenylmethyl; those of the formula —COOR where R includes such groupsas methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl,1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl,benzyl, p-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acylgroups and substituted acyl such as formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, andp-methoxybenzoyl; and other groups such as methanesulfonyl,p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrophenylethyl, andp-toluenesulfonyl-aminocarbonyl. Preferred amino-blocking groups arebenzyl (—CH₂C₆H₅), acyl [C(O)R] or SiR₃ where R is C₁-C₄ alkyl,halomethyl, or 2-halo-substituted-(C₂-C₄ alkoxy), aromatic urethaneprotecting groups as, for example, carbonylbenzyloxy (Cbz); andaliphatic urethane protecting groups such as t-butyloxycarbonyl (Boc) or9-fluorenylmethoxycarbonyl (FMOC).

[0161] A set of preferred reagents for installing end cap units onamines include: ethanoyl chloride (Acy); 2,2-dimethylpropanoyl chloride(Piv); naphthalenecarbonyl chloride (Nap); 1 ,3-benzodioxole-5-carbonylchloride (Pip); methyl 2-chlorocarbonylacetate (Mal); pipicolic or2-pyridinecarboxylic acid (Pic); 5-oxo-2-pyrrolidinecarboxylic acid(Pga); 4-methyl-1-benzenesulfonyl chloride (Tos); and phenylmethanamide(ICN).

[0162] To incorporate amino- and/or carboxyl-protecting groups,conventional solid phase peptide synthesis methods and otherconventional techniques can also be adapted to the subject method.Incorporation of amino-blocking group, for example, can be achievedwhile the synthesized compound is still attached to the resin, forinstance by treatment with a suitable anhydride. To incorporate anacetyl protecting group, for instance, the resin-coupled coupled can betreated with 20% acetic anhydride.

[0163] IV. Detection of Catalytic Activity

[0164] Libraries of potential catalysts can be screened for catalyticactivity according to a variety of techniques, some of which are knownin the art. If a transformation catalyzed by a catalyst of the subjectmethod is accompanied by a detectable event, e.g. the formation of aprecipitate, the evolution of a gas, or the emission of a photon, thecombination of the catalyst and the detectable event may form the basisof a test for the presence, in a sample or a complex mixture, of thecatalyst's substrate. Conversely, exposure of a library of potentialcatalysts to a known substrate for a desired type of catalytic activity,wherein the substrate during or upon transformation by a catalystgenerates a detectable event, may form the basis of a screening methodfor that type of catalytic activity.

[0165] Libraries of potential catalysts can also be screened withreagents which detect functional properties of a catalyst or catalysts.For example, a probe moiety can be combined with a label moiety, such asa dye, a fluorophore, a radiolabel, or the like, to detect the presenceof a target (e.g., by staining a bead). The probe can bind reversibly orirreversibly to the target. For example, a library of potentialcatalysts may be screened for the presence of Lewis-acidic moieties bycontacting the library with a compound, e.g., a compound comprising aLewis basic functional group, which interacts reversibly with such Lewisacids, and in which the compound comprises additionally a label moiety.Any potential catalyst which comprises a Lewis-acidic moiety will thenbecome associated, through the Lewis basic moiety, with a label, whichin turn can be detected.

[0166] The subject methods may be utilized to discover and optimizecatalysts for a wide range of chemical transformations. Catalysts may bediscovered and optimized for transformations selected from the setcomprising kinetic resolutions, regioselective reactions, chemoselectivereactions, diastereoselective reactions, stereoselective reactions,functional group interconversions, hydrogenations, oxidations,reductions, resolutions of racemic mixtures, cycloadditions, sigmatropicrearrangements, electrocyclic reactions, ring-openings, crbonyladditions, carbonyl reductions, olefin additions, olefin reductions,imine additions, imine reductions, olefin epoxidations, olefinaziridinations, carbon-carbon bond formations, carbon-heteroatom bondformations, and heteroatom-heteroatom bond formations.

[0167] V Tagging/Deconvolution Techniques for Libraries

[0168] A) Direct Characterization

[0169] A growing trend in the field of combinatorial chemistry is toexploit the sensitivity of techniques such as mass spectrometry (MS),e.g., which can be used to characterize sub-femtomaolar amounts ofcompound, and to directly determine the chemical constitution of acompound selected from a combinatorial library. For instance, where thelibrary is provided on an insoluble support matrix, discrete populationsof compounds can be first released from the support and characterized byMS. In other embodiments, as part of the MS sample preparationtechnique, such MS techniques as MALDI can be used to release a compoundfrom the matrix, particularly where a labile bond is used originally totether the compound to the matrix. For instance, a bead selected fromthe a potential catalyst library can be irradiated in a MALDI step inorder to release the potential catalyst from the matrix and ionize thepotential catalyst for MS analysis.

[0170] B) Multipin Synthesis

[0171] One form that the potential catalyst library of the subjectmethod can take is the multipin library fornat. Briefly, Geysen andco-workers (Geysen et al. (1984) PNAS 81:3998-4002) introduced a methodfor generating compound libraries by a parallel synthesis on polyacrylicacid-grated polyethylene pins arrayed in the microtitre plate format.The Geysen technique can be used to synthesize and screen thousands ofpotential catalysts per week using the multipin method, and the tetheredpotential catalysts may be reused in many assays. Appropriate linkermoieties can also been appended to the pins so that the potentialcatalysts may be cleaved from the supports after synthesis forassessment of purity and further evaluation (cf, Bray et al. (1990)Tetrahedron Lett 31:5811-5814; Valerio et al. (1991) Anal Biochem197:168-177; Bray et al. (1991) Tetrahedron Lett 32:6163-6166).

[0172] C) Divide-Couple-Recombine

[0173] In yet another embodiment, a variegated library of potentialcatalysts can be provided on a set of beads utilizing the strategy ofdivide-couple-recombine (see, e.g., Houghten (1985) PNAS 82:5131-5135;and U.S. Pat. Nos. 4,631,211; 5,440,016; 5,480,971). Briefly, as thename implies, at each synthesis step where degeneracy is introduced intothe library, the beads are divided into separate groups equal to thenumber of different substituents to be added at a particular position inthe potential catalyst library, the different substituents coupled inseparate reactions, and the beads recombined into one pool for the nextiteration.

[0174] In one embodiment, the divide-couple-recombine strategy can becarried out using an analogous approach to the so-called “tea bag”method first developed by Houghten, where potential catalyst synthesisoccurs on resin sealed inside porous polypropylene bags (Houghten et al.(1986) PNAS 82:5131-5135). Substituents are coupled to the potentialcatalyst-bearing resins by placing the bags in appropriate reactionsolutions, while all common steps such as resin washing and deprotectionare performed simultaneously in one reaction vessel. At the end of thesynthesis, each bag contains a single potential catalyst moiety.

[0175] D) Combinatorial Libraries by Light-Directed, SpatiallyAddressable Parallel Chemical Synthesis

[0176] A scheme of combinatorial synthesis in which the identity of acompound is given by its locations on a synthesis substrate is termed aspatially-addressable synthesis. In one embodiment, the combinatorialprocess is carried out by controlling the addition of a chemical reagentto specific locations on a solid support (Dower et al. (1991) Annu RepMed Chem 26:271-280; Fodor, S. P. A. (1991) Science 251:767; Pirrung etal. (1992) U.S. Pat. No. 5,143,854; Jacobs et al. (1994) TrendsBiotechnol 12:19-26). The spatial resolution of photolithography affordsminiaturization. This technique can be carried out through the useprotection/deprotection reactions with photolabile protecting groups.

[0177] The key points of this technology are illustrated in Gallop etal. (1994) J Med Chem 37:1233-1251. A synthesis substrate is preparedfor coupling through the covalent attachment of photolabilenitroveratryloxycarbonyl (NVOC) protected amino linkers or otherphotolabile linkers. Light is used to selectively activate a specifiedregion of the synthesis support for coupling. Removal of the photolabileprotecting groups by light (deprotection) results in activation ofselected areas. After activation, the first of a set of amino acidanalogs, each bearing a photolabile protecting group on the aminoterminus, is exposed to the entire surface. Coupling only occurs inregions that were addressed by light in the preceding step. The reactionis stopped, the plates washed, and the substrate is again illuminatedthrough a second mask, activating a different region for reaction with asecond protected building block. The pattern of masks and the sequenceof reactants define the products and their locations. Since this processutilizes photolithography techniques, the number of compounds that canbe synthesized is limited only by the number of synthesis sites that canbe addressed with appropriate resolution. The position of each potentialcatalyst is precisely known; hence, its interactions with othermolecules can be directly assessed.

[0178] In a light-directed chemical synthesis, the products depend onthe pattern of illumination and on the order of addition of reactants.By varying the lithographic patterns, many different sets of testpotential catalysts can be synthesized simultaneously; thischaracteristic leads to the generation of many different maskingstrategies.

[0179] E) Encoded Combinatorial Libraries

[0180] In yet another embodiment, the subject method utilizes apotential catalyst library provided with an encoded tagging system. Arecent improvement in the identification of active compounds fromcombinatorial libraries employs chemical indexing systems using tagsthat uniquely encode the reaction steps a given bead has undergone and,by inference, the structure it carries. Conceptually, this approachmimics phage display libraries, where activity derives from expressedpeptides, but the structures of the active peptides are deduced from thecorresponding genomic DNA sequence. The first encoding of syntheticcombinatorial libraries employed DNA as the code. A variety of otherforms of encoding have been reported, including encoding withsequenceable bio-oligomers (e.g., oligonucleotides and peptides), andbinary encoding with additional non-sequenceable tags.

[0181] 1) Tagging with Sequenceable Bio-Oligomers

[0182] The principle of using oligonucleotides to encode combinatorialsynthetic libraries was described in 1992 (Brenner et al. (1992) PNAS89:5381-5383), and an example of such a library appeared the followingyear (Needles et al. (1993) PNAS 90:10700-10704). A combinatoriallibrary of nominally 7⁷ (=823,543) peptides composed of all combinationsof Arg, Gln, Phe, Lys, Val, D-Val and Thr (three-letter amino acidcode), each of which was encoded by a specific dinucleotide (TA, TC, CT,AT, TT, CA and AC, respectively), was prepared by a series ofalternating rounds of peptide and oligonucleotide synthesis on solidsupport. In this work, the amine linking functionality on the bead wasspecifically differentiated toward peptide or oligonucleotide synthesisby simultaneously preincubating the beads with reagents that generateprotected OH groups for oligonucleotide synthesis and protected NH₂groups for peptide synthesis (here, in a ratio of 1:20). When complete,the tags each consisted of 69-mers, 14 units of which carried the code.The bead-bound library was incubated with a fluorescently labeledantibody, and beads containing bound antibody that fluoresced stronglywere harvested by fluorescence-activated cell sorting (FACS). The DNAtags were amplified by PCR and sequenced, and the predicted peptideswere synthesized. Following such techniques, potential catalystlibraries can be derived for use in the subject method, where theoligonucleotide sequence of the tag identifies the sequentialcombinatorial reactions that a particular bead underwent, and thereforeprovides the identity of the potential catalyst on the bead.

[0183] The use of oligonucleotide tags permits exquisitely sensitive taganalysis. Even so, the method requires careful choice of orthogonal setsof protecting groups required for alternating co-synthesis of the tagand the library member. Furthermore, the chemical lability of the tag,particularly the phosphate and sugar anomeric linkages, may limit thechoice of reagents and conditions that can be employed for the synthesisof non-oligomeric libraries. In preferred embodiments, the librariesemploy linkers permitting selective detachment of the test potentialcatalyst library member for assay.

[0184] Peptides have also been employed as tagging molecules forcombinatorial libraries. Two exemplary approaches are described in theart, both of which employ branched linkers to solid phase upon whichcoding and ligand strands are alternately elaborated. In the firstapproach (Kerr J M et al. (1993) J Am Chem Soc 115 :2529-2531),orthogonality in synthesis is achieved by employing acid-labileprotection for the coding strand and base-labile protection for theligand strand.

[0185] In an alternative approach (Nikolaiev et al. (1993) Pept Res6:161-170), branched linkers are employed so that the coding unit andthe test potential catalyst can both be attached to the same functionalgroup on the resin. In one embodiment, a cleavable linker can be placedbetween the branch point and the bead so that cleavage releases amolecule containing both code and the potential catalyst (Ptek et al.(1991) Tetrahedron Lett 32:3891-3894). In another embodiment, thecleavable linker can be placed so that the test potential catalyst canbe selectively separated from the bead, leaving the code behind. Thislast construct is particularly valuable because it permits screening ofthe test potential catalyst without potential interference of the codinggroups. Examples in the art of independent cleavage and sequencing ofpeptide library members and their corresponding tags has confirmed thatthe tags can accurately predict the peptide structure.

[0186] 2) Non-Sequenceable Tagging: Binary Encoding

[0187] An alternative form of encoding the test potential catalystlibrary employs a set of non-sequencable electrophoric tagging moleculesthat are used as a binary code (Ohlmeyer et al. (1993) PNAS90:10922-10926). Exemplary tags are haloaromatic alkyl ethers that aredetectable as their trimethylsilyl ethers at less than femtomolar levelsby electron capture gas chromatography (BCGC). Variations in the lengthof the alkyl chain, as well as the nature and position of the aromatichalide substituents, permit the synthesis of at least 40 such tags,which in principle can encode 2⁴⁰ (e.g., upwards of 10¹²) differentmolecules. In the original report (Ohlmeyer et al., supra) the tags werebound to about 1% of the available amine groups of a peptide library viaa photocleavable o-nitrobenzyl linker. This approach is convenient whenpreparing combinatorial libraries of peptide-like or otheramine-containing molecules. A more versatile system has, however, beendeveloped that permits encoding of essentially any combinatoriallibrary. Here, the potential catalyst would be attached to the solidsupport via the photocleavable linker and the tag is attached through acatechol ether linker via carbene insertion into the bead matrix(Nestler et al. (1994) J Org Chem 59:4723-4724). This orthogonalattachment strategy permits the selective detachment of library membersfor assay in solution and subsequent decoding by ECGC after oxidativedetachment of the tag sets.

[0188] Although several amide-linked libraries in the art employ binaryencoding with the electrophoric tags attached to amine groups, attachingthese tags directly to the bead matrix provides far greater versatilityin the structures that can be prepared in encoded combinatoriallibraries. Attached in this way, the tags and their linker are nearly asunreactive as the bead matrix itself. Two binary-encoded combinatoriallibraries have been reported where the electrophoric tags are attacheddirectly to the solid phase (Ohlmeyer et al. (1995) PNAS 92:6027-6031)and provide guidance for generating the subject potential catalystlibrary. Both libraries were constructed using an orthogonal attachmentstrategy in which the library member was linked to the solid support bya photolabile linker and the tags were attached through a linkercleavable only by vigorous oxidation. Because the library members can berepetitively partially photoeluted from the solid support, librarymembers can be utilized in multiple assays. Successive photoelution alsopermits a very high throughput iterative screening strategy: first,multiple beads are placed in 96-well microtiter plates; second, ligandsare partially detached and transferred to assay plates; third, a metalbinding assay identifies the active wells; fourth, the correspondingbeads are rearrayed singly into new microtiter plates; fifth, singleactive potential catalysts are identified; and sixth, the structures aredecoded.

[0189] F) Selection of Potential Catalysts Based on ThermographicTechniques

[0190] In certain embodiments, libraries of potential catalysts will bescreened using thermographic techniques (for a recent example of thisstrategy, see: Taylor and Morken, Science 1998, 280, 267-270). Thistechnology constitutes a general method for the rapid and simultaneousevaluation of each member of large encoded catalyst libraries for theability to catalyze a given reaction in solution. This technologyenables the selection of active catalysts from a library ofpolymer-bound multifunctional potential catalysts. For example, Taylorand Morken disclosed that from ˜7000 beads screened (3150 distinctcatalysts), 23 beads were selected for catalysis of an acylationreaction. Their kinetic experiments indicated that the most stronglyselected beads were also the most efficient catalysts.

[0191] VI. Reaction Conditions

[0192] In one aspect of the invention, the subject screening method canbe carried out utilizing immobilized potential catalyst libraries. Thechoice of a suitable polymeric support will be routine to the skilledartisan. In general, the polymeric support will be selected according toat least some of the following criteria: (i) it should not be reactiveunder conditions used for detecting catalytic activity; and (ii) it willhave little to no background catalytic activity. The potential catalystscan be derivatized to the polymeric support utilizing appropriatefunctional groups and methods known in the art. Those embodiments whichemploy some form of matrix immobilization of the potential catalystlibrary are amenable to the use of encoding and/or spatial addressing ofthe library for later deconvolution.

[0193] Insoluble polymeric supports include functionalized polymersbased on polystyrene, polystyreneldivinylbenzene copolymers, and otherpolymers known to the skilled artisan. It will be understood that thepolymeric support can be coated, grafted, or otherwise bonded to othersolid supports.

[0194] In another embodiment, the polymeric support can be provided byreversibly soluble polymers. Such polymeric supports includefunctionalized polymers based on polyvinyl alcohol or polyethyleneglycol (PEG). A soluble support can be made insoluble (e.g., can be madeto precipitate) by addition of a suitable inert non-solvent. Oneadvantage of reactions performed using soluble polymeric supports isthat reactions in solution can be more rapid, higher yielding, and/ormore complete than reactions that are performed on insoluble polymericsupports. Accordingly, in preferred embodiments, the polymer support isPEG or PEG-OMe.

[0195] In still other embodiments, the potential catalyst library can besynthesized in solution, and by the use of deconvolution techniques, orsynthesis in multiple reaction vessels (e.g., microtitre plates and thelike), the identity of particular members of the library can bedetermined.

[0196] VII. Catalysts for Stereoselective Nucleophilic Reaction, andExemplary Uses Thereof

[0197] As described in further detail below, the subject combinatorialmethod has been employed to generate a novel class of catalyst usefulfor, e.g., the addition of a nucleophile across a reactive π-bond.

[0198] In general, the invention features a stereoselective nucleophilicaddition process which comprises combining a substrate comprising areactive π-bond, a nucleophile, and at least a catalytic amount of anon-racemic, chiral catalyst of particular characteristics (as describedbelow). The combination is maintained under conditions appropriate forthe chiral catalyst to catalyze stereoselective addition of thenucleophile to the reactive π-bond of the substrate. This reaction canbe applied to enantioselective processes as well as diastereoselectiveprocesses. It may also be adapted for regioselective reactions. Examplesfollow of enantioselective reactions, kinetic resolution, andregioselective reactions which may be catalyzed according to the presentinvention.

[0199] In an exemplary and preferred embodiment, cyanide ion adds to thecarbon of an imine functional group in the presence of the subjectchiral, non-racemic catalyst yielding a non-racemic α-amino nitrileproduct. This embodiment is an example of a subject enantioselectivenucleophilic addition reaction, and can be represented by the generaltransformation:

[0200] wherein

[0201] R₁₀₀, R₁₀₁, and R₁₀₂ represent, independently for eachoccurrence, hydrogen, alkyl, alkenyl, alkynyl, acyl, thioacyl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide,hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate,urea, thiourea, or —(CH₂)_(m)—R_(80,) or

[0202] R₁₀₂, along with the imine carbon and nitrogen, and either R₁₀₀or R₁₀₁, form a heterocycle (substituted or unsubstituted) having from 4to 10 atoms, subject to geometric constraints, in the ring structure, or

[0203] R₁₀₀ and R₁₀₁ together form a ring (substituted or unsubstituted)having from 4 to atoms in the ring structure;

[0204] R₈₀ represents an unsubstituted or substituted aryl, acycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;

[0205] m is an integer in the range 0 to 8 inclusive; and

[0206] HCN represents hydrogen cyanide or its surrogate, e.g., potassiumcyanide, sodium cyanide, acetone cyanohydrin, or trimethylsilyl cyanide.

[0207] According to the above reaction scheme, and other reactions andstructures recited herein, the designation “*” next to a carbon atomindicates a (potential) chiral center.

[0208] The addition of cyanide to imines (the Strecker reaction)constitutes one of the most direct and viable strategies for theasymmetric synthesis of α-amino acid derivatives. Significant progresshas been made in the development of stereoselective versions of thisreaction using imines bearing covalently attached chiral auxiliaries.However, despite the obvious practical potential of an enantioselectivecatalytic version of the Strecker reaction, only limited success hasbeen attained to this end. In contrast, as described in the appendedexamples, we describe herein novel chiral catalysts which catalyzeenantioselective Strecker reactions.

[0209] In a preferred embodiment, the Strecker catalyst of the presentinvention is represented by the general formula:

[0210] wherein

[0211] B represents a monocyclic or polycyclic group (e.g., acycloalkyl, heterocycle, aromatic or heteroaromatic ring);

[0212] C₁, C₂ and C₃ each represent chiral carbon atoms;

[0213] X represents O, S or NH;

[0214] J represents a linker group including at least one functionalgroup capable of acting as a hydrogen bond donor, e.g., a weak Bronstedacid;

[0215] R₁₀₃ represents either a hydrogen bond donor, a Lewis basicgroup, or a group with both characteristics;

[0216] R₁₀₄ represents a sterically bulky, aliphatic or cycloaliphaticsubstituent of up to 20 carbons (preferably 2-10), e.g., whichsterically hinders the Lewis basic group such that it remains disposedin proximity to a catalytic active site including the imine nitrogen ofthe catalyst and J;

[0217] R₁₀₅ is absent, or represents one or more additional substituentsof B selected from the group consisting of alkyl, alkenyl, alkynyl,acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate,phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine,carbarnate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R_(80;) and

[0218] R₁₀₆ and R₁₀₇ each independently represent alkyl, alkenyl,alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl,aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime,sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R_(80,) or

[0219] R₁₀₆ and R₁₀₇ taken together with C₂ and C₃ form a ring havingfrom 4 to 8 atoms in the ring;

[0220] R₁₀₈ and R₁₀₉ each independently represent an alkyl, representalkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide,phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide,anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl,ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl,heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide,oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R_(80,) with the proviso that R₁₀₈ and (C(X)R₁₀₉) are notidentical (this proviso is implied by the chirality of C₁);

[0221] R₈₀ represents an unsubstituted or substituted aryl, acycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and

[0222] m is an integer in the range 0 to 8 inclusive.

[0223] In preferred embodiments, X is S or O.

[0224] In preferred embodiments, R₁₀₃ is —NH₂, —OH, or —SH, or a loweralkyl group substituted thereby.

[0225] In preferred embodiments, R₁₀₄ is attached to B at a positionortho to R₁₀₃, and meta to the imine substituent. R₁₀₄ is preferably alower alkyl or alkoxyl group, e.g., a branched lower alkyl such as at-butyl group.

[0226] In preferred embodiments, R₁₀₆ and R₁₀₇ are C₃-C₈ alkyl groups,or, together with C₂ and C₃ form a ring having from 4 to 8 atoms in thering.

[0227] In preferred embodiments, J is represented by —NH—Y—NH—, whereinY is selected from the group consisting of

[0228] wherein Q₁ represents S or O, and R₄₆ represents hydrogen, alower alkyl or an aryl. In more preferred embodiments, Y is selectedfrom the group consisting of —C(=Q₁)—, wherein Q₁ is O or S.

[0229] In certain embodiments, R₁₀₈ represents an alkyl, heteroalkyl,aryl or heteroaryl group.

[0230] In preferred embodiments, R₁₀₈ represents a side-chain of anaturally occurring α-amino acid or analog thereof.

[0231] In certain embodiments, R₁₀₉ represents an amino group, e.g., aprimary or secondary amino group, through preferably a primary aminogroup. For example, R₁₀₉ can be represented by

[0232] wherein R₉ and R₁₀ each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R₈₀, or R₉ and R₁₀ taken together with theN atom to which they are attached complete a heterocycle having from 4to 8 atoms in the ring structure, or R₉ or R₁₀ can represent a linkerand solid support matrix; R₈₀ and m being defined above.

[0233] The presence of bulky substituents at one or more of R₁₀₄, R₁₀₅,R₁₀₆, R₁₀₇ and/or R₁₀₈ can have a marked effect on selectivity, andthese groups may improve stereochemical communication between thesubstrate(s) and the catalyst in the transition state.

[0234] In preferred embodiments, the Strecker catalyst of the presentinvention is represented by the general formula:

[0235] wherein

[0236] B, X, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₈, and R₁₀₉ are defined above;

[0237] A represents a monocyclic or polycyclic group (e.g., acycloalkyl, heterocycle, aryl or heteroaryl ring); and

[0238] R₁₁₀ is absent, or represents one or more additional substituentsof A selected from the group consisting of alkyl, alkenyl, alkynyl,acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate,phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀.

[0239] In preferred embodiments, A is a cycloalkyl having from 3-10carbon atoms in its ring structure, and more preferably have 5, 6 or 7carbons in the ring structure.

[0240] In additional preferred embodiments, the catalysts of the subjectinvention are represented by the following general structure:

[0241] wherein

[0242] X represents, independently for each occurrence, O, S, or NR;

[0243] R, R₁, R₂, and R₃ represent, independently for each occurrence,H, alkyl, aryl, heteroalkyl, or heteroaryl;

[0244] R₄ represents H, alkyl, heteroalkyl, aryl, heteroaryl, formyl, oracyl;

[0245] R₂ is absent or occurs no more than 4 times; and

[0246] n is an integer selected from the range 0 to 2 inclusive.

[0247] In highly preferred embodiments, the general structure aboveapplies:

[0248] wherein

[0249] X represents, independently for each occurrence, O or S;

[0250] R, R₁, R₂, and R₃ represent, independently for each occurrence,H, alkyl, aryl, heteroalkyl, or heteroaryl;

[0251] R₄ represents alkyl, heteroalkyl, aryl, or heteroaryl;

[0252] R₂ is absent; and

[0253] n is an integer selected from the range 0 to 2 inclusive.

[0254] In additional highly preferred embodiments, the general structureabove applies:

[0255] wherein

[0256] X represents, independently for each occurrence, O or S;

[0257] R, R₁, R₂, and R₃ represent, independently for each occurrence,H, alkyl, aryl, heteroalkyl, or heteroaryl;

[0258] R₄ represents formyl or acyl;

[0259] R₂ is absent; and

[0260] n is an integer selected from the range 0 to 2 inclusive.

[0261] In preferred embodiments, the catalysts of the subject inventioncatalyze at least one stereoselective nucleophilic addition with anenantioselectivity of at least 75% ee, more preferably at least 80% ee,85% ee, 90% ee, 95%ee or even>98% ee.

[0262] The asymmetric Strecker reaction according to the methods of thepresent invention provides a straightforward entry into enantiomericallyenriched α-amino acid derivatives from readily available substrate andcatalyst precursors using low catalyst loading. The catalyst is easilyprepared on large scale and appears to have an indefinite “shelf life”even when stored under ambient conditions.

[0263] In an exemplary embodiment, cyanide ion adds to the carbon of animine functional group in the presence of a subject chiral, non-racemiccatalyst yielding a non-racemic α-amino nitrile product. This embodimentis an example of a subject enantioselective nucleophilic additionreaction. The product of this reaction can be transformed in a singlestep to non-racemic N-methyl phenylglycine—a non-natural α-amino acid.

[0264] To further illustrate, N-allyl-2-naphthylmethanimine can bereacted with HCN to generate the corresponding nitrile, which in turncan be reacted with MeOH in the presence of acid to yield the methylester. The allyl group can be subsequently removed with, e.g.,dimethylbarbituric acid and catalytic palladium(O), to yield the α-aminoester. Recrystallization can be used to further increase the purity ofthe single enantiomer.

[0265] Another illustrative example of the use of the subject catalystsincludes the enantioselective conversion of sulfinimines tosulfinamides, e.g., as shown in the reaction scheme below. The resultingsulfinamide can be further converted into a primary amine which containsa new stereogenic center.

[0266] To provide another illustration, the aniline in the reactionshown below (see, e.g., U.S. Pat. No. 5,661,160) is reacted with cyanidein the presence of the subject catalyst to yield a nitrile.

[0267] In a further aspect of the present invention, a nucleophile maybe added to an endocyclic imine as shown below.

[0268] In another aspect of the invention, the nucleophilic additionreaction occurs in a diastereoselective manner in the presence of thesubject chiral, non-racemic catalyst. An illustrative example of adiastereoselective reaction of the present invention is shown below.

[0269] In another illustrative embodiment, the present inventionprovides a method for the kinetic resolution of a racemic mixture of animine containing an α-stereocenter. In the subject catalyst-mediatedkinetic resolution process involving a racemic imine substrate, oneenantiomer of the imine can be recovered as unreacted substrate whilethe other is transformed to the desired product. This aspect of theinvention provides methods of synthesizing functionalized non-racemicproducts from racemic starting materials. This embodiment is adiastereoselective process as well.

[0270] A second type of kinetic resolution possible with the subjectcatalysts involves the resolution of a racemic nucleophile. Theexemplary embodiment shown below centers on the resolution of a racemicmixture of thiols in catalyzed reaction with O-methyl benzophenoneoxime. Use of approximately 0.5 equivalents of the oxime ether in thesubject method will provide a product mixture comprising bothnon-racemic unreacted thiol and a non-racemic addition product.

[0271] Skilled artisans will recognize that the subject invention can beapplied to substrates comprising two reactive π-bonds of differingreactivity. The illustrative embodiment below involves a diiminesubstrate wherein the imines differ in their steric environments; thesubject method is expected, all other factors being equal, to catalyzeselectively nucleophilic addition at the less hindered imine moiety.

[0272] Additionally, skilled artisans will recognize that the subjectinvention can be applied to substrates comprising different classes ofreactive π-bonds. The illustrative embodiment below involves a substratethat comprises both an imine and a hydrazone. The subject method isexpected, all other factors being equal, to catalyze nucleophilicaddition at the imine moiety.

[0273] The subject method and catalysts may also be exploited in anintramolecular sense. In the illustrative embodiment that follows, thechiral, non-racemic catalyst may catalyze the intramolecularenantioselective addition of a thiol to an N-allyl imine.

[0274] The processes of this invention can provide optically activeproducts with very high stereoselectivity (e.g., enantioselectivity ordiasteroselectivity) or regioselectivity. In preferred embodiments ofthe subject enantioselective reactions, enantiomeric excesses ofpreferably greater than 50%, more preferably greater than 75% and mostpreferably greater than 90% can be obtained by the processes of thisinvention. Likewise, with respect to regioselective reactions, molarratios for desired/undesired regioisomers of preferably greater than5:1, more preferably greater than 10:1 and most preferably greater than25:1 can be obtained by the processes of this invention. The processesof this invention can also be carried out at highly desirable reactionrates suitable for commercial use.

[0275] As is clear from the above discussion, the chiral productsproduced by the asymmetric synthesis processes of this invention canundergo further reaction(s) to afford desired derivatives thereof. Suchpermissible derivatization reactions can be carried out in accordancewith conventional procedures known in the art. For example, potentialderivatization reactions include epoxidation, ozonolysis, halogenation,hydrohalogenation, hydrogenation, esterification, oxidation of alcoholsto aldehydes, ketones and/or carboxylate derivatives, N-alkylation ofamides, addition of aldehydes to amides, nitrile reduction, acylation ofalcohols by esters, acylation of amines and the like. To furtherillustrate, exemplary classes of pharmaceuticals which can besynthesized by a scheme including the subject stereoselective reactionare cardiovascular drugs, nonsteroidal antiinflammatory drugs, centralnervous system agents, and antihistaminics.

[0276] VIII. Exemplification

[0277] The invention now being generally described, it will be morereadily understood by reference to the following examples which areincluded merely for purposes of illustration of certain aspects andembodiments of the present invention, and are not intended to limit theinvention.

EXAMPLE 1

[0278] This example outlines the application of parallel combinatoriallibrary synthesis to the discovery and optimization of a chiral catalystfor the formal addition of hydrogen cyanide to imines (the Streckerreaction). Through an iterative sequence involving the preparation andevaluation of 3 solid phase libraries containing a total of 192compounds, optimization of reaction enantioselectivity Was achieved froman initial lead result of 19% ee up to 91% ee. The catalyst identifiedthrough optimization for the hydrocyanation of N-allybenzaldimine provedeffective for a range of imine substrates. In particular, >80% ee wasachieved for the first time with any catalyst system for the Streckerreaction of aliphatic imines. The structural features that lead to highenantioselectivity are quite unanticipated, with non-intuitivesynergistic effects displayed between catalyst components.

[0279] Combinatorial chemistry is now well-recognized as a promisingstrategy for the discovery and optimization of ligands for biologicaltargets, and it has more recently emerged as a viable approach towardthe identification of novel catalysts,¹ coordination complexes,² andsolid-state materials.³ Two fundamentally differentstrategies—split-and-pool, and parallel library synthesis—can bedistinguished within combinatorial chemistry, and the choice of methoddepends on the problem at hand.⁴ The split-and-pool strategy may beadvantageous when it is desirable or even necessary to evaluate largenumbers of compounds because little is known about the target structureand the proportion of compounds with the sought-after activity is likelyto be extremely low.⁵ The parallel library approach can be most viablefor lead optimization, where the basic features of the target structurehave already been established.⁶ In this case, the greater experimentalsimplicity associated with screening and identifying spatially arrayedcandidate structures can override the possible advantages associatedwith evaluating larger libraries. We have explored this latter scenarioin the context of asymmetric catalysis, with the synthesis of parallelcombinatorial libraries of a known class of chiral ligands,⁷ and theirevaluation as catalysts for the asymmetric hydrocyanation of imines (theStrecker reaction) (eq. 1). In this paper, the viability of the approachis illustrated by the iterative optimization of reactionenantioselectivity from an initial lead result of 19% ee to 91% eethrough a sequence of non-obvious modifications in the catalyststructure.

[0280] Equation 1

[0281] The initial step in the implementation of the parallel catalystlibrary strategy was the selection of a potential catalyst system thatwas amenable to solid phase synthesis and systematic structuralvariation, and also known to be a selective template for chiralitytransfer. These stipulations dictate high-yielding and generalizablesynthetic access to the catalyst with an unobtrusive site for attachmentto the solid support. Unfortunately, these criteria are not all met inmost of the best known and most effective chiral ligand systems, such asbinaphthyl-based ligands, C2 symmetric phosphines, salen ligands,bisoxazolines, and tartrate- and cinchona alkaloid-derived compounds. Incontrast, tridentate Schiff base complexes constitute an emerging classof catalysts⁸ that might be amenable to solid phase synthesis. Thesesystems are typically comprised of 3 units, a chiral amino alcohol, asalicylaldehyde derivative, and a metal. We chose to modify the corestructure such that the amino alcohol was replaced with a diamine, withthe second nitrogen on the chiral backbone serving as the site forattachment to the solid support (FIG. 1). An amino acid was incorporatedas an additional diversity element between the diamine and the polymersupport. The resulting ligand system was evaluated and optimized for thereaction in eq. 1 by carrying out the transformations in parallel withthe polymer supported catalysts in individual reaction vessels,⁹ andassaying the product mixtures with a commercial autosampler by chiral GCanalysis.

[0282] Library 1:

[0283] One ligand of the type in FIG. 1 was prepared and evaluated forcatalysis of addition of TBSCN to N-allylbenzaldimine in the presence ofa series of different metal ions (see FIG. 2 for the structures of thecatalysts of Libraries 1-3). Whereas comparable reactivity was observedin each case, ligand in the absence of any added metal ion proved to bethe most enantioselective (19% ee).

[0284] Library 2

[0285] Based upon this initial lead result, a parallel ligand library of48 members was prepared and screened in the absence of any added metalions (see FIG. 3). The amino acid component was observed to exert a verysignificant effect on reaction enantioselectivity, with leucine-derivedcatalysts providing the best results. The relative stereochemistry ofthe catalyst was also important, with (R,R)-diamine-derived catalystsaffording substantially higher ee's when coupled with L-leucine thanwith the unnatural D-leucine enantiomer (e.g. Leu-CH-D: 32% ee;D-Leu-CH-D: 5% ce). Finally, the substituents on the salicylaldehydederivatives were also found to play a critical role, with t-butylsubstituted derivatives A, B, and D affording highest ee's.

[0286] At this stage of the development of the catalyst libraries, thelinker elements (see FIG. 1) were optimized by a classical,one-catalyst-at-a-time, approach. Control experiments revealed that thecaproic acid unit used to link the catalyst to the resin in Libraries 1and 2 (Linker₁) was responsible for a non-negligible level of backgroundreactivity. Direct attachment of the amino acid group of the catalyst tothe polystyrene support resulted in improved enantioselectivity for thebest catalysts identified from Library 2 (e.g. 30% to 45% ee withLeu-CH-A). The unit used to link the amino acid to the diamine (Linker₂)was also found to influence catalyst enantioselectivity. For example, inthe Leu-CH-A series, replacement of the urea linker with thiourea led toan enhancement in ee from 45% to 55%, whereas the correspondingguanidine-linked system effected the same Strecker reaction with only21% ee.

[0287] Library 3

[0288] On the basis of the results obtained from Library 2, a largerparallel library of 132 thiourea derivatives was prepared incorporatingonly non-polar L-amino acids and 3-t-butyl substituted salicylaldehydederivatives. All library members were found to catalyze the reaction ineq. 1, with t-Leu-CH-OMe (OMe denoting3-t-butyl-5-methoxysalicylaldehyde, D in Library 2) affording thehighest enantioselectivity (80% ee, see FIG. 4). The amino acidcomponent was again seen to be crucial, with the bulkiest derivatives(t-Leu, cyclohexylglycine, and isoleucine) providing best results.Interestingly, t-Leu proved to be the best amino acid component forCH-derived catalysts, but the worst one for CP derivatives, effectivelyhighlighting the benefit of evaluating all ligand permutations.

[0289] The best catalysts identified from the library screens,t-Leu-CH-OMe (1) and 2, were synthesized independently in solution andtested in the asymmetric reactions in eqs. 2 and 3. With HCN as thecyanide source, the solution-phase catalyst 1 catalyzed the formation ofthe Strecker adduct of N-allylbenzaldimine in 78% isolated yield and 91%ee at −78° C. Even though 1 was optimized for that particular substrate,it proved to be an effective catalyst for a range of imine derivatives,affording product with moderate-to-high enantioselectivity and yield(Table 1). It is especially noteworthy that aliphatic imine derivatives(Table 1, entries e and f; Table 2, entries 2-4) underwenthydrocyanation with >80% ee. These results constitute the first examplesof high enantioselectivity in the Strecker reaction with this importantclass of substrates.¹⁰

[0290] Equation 2

TABLE 1 Entry R yield(%)^(a) ee(%)^(b) a Ph 78 91 b ρ-OCH₃C₆H₄ 92 70 cρ-BrC₆H₄ 65 86 d 2-Napthyl 88 88 e t-Butyl 70 85 f Cyclohexyl 77 83

[0291] Equation 3

TABLE 2 Results Obtained According to Equation 3. Imine StartingMaterial ee of Product (%) 1

95 2

87 3

95 4

95

[0292] These studies demonstrate that chiral Schiff bases identifiedfrom parallel synthetic libraries can be effective asymmetric catalystsfor the Strecker reaction. These systems not only exhibit promisingenantioselectivity both on solid phase and in solution, but are alsoeasily prepared from inexpensive components. The structural featuresthat lead to high enantioselectivity are quite unanticipated, withnon-intuitive synergistic effects displayed between catalyst components.These results raise interesting questions concerning the mechanism ofcatalysis of the hydrocyanation reaction. Experiments are in progress toaddress this issue, to further develop this new class of catalysts forthe Strecker reaction, and finally to identify effective asymmetriccatalysts for other important reactions using this parallel approach.

NOTES AND REFERENCES

[0293] (1) For reviews and discussions, see: (a) Gennari, C.; Nestler,H. P.; Piarulli, U.; Salom, B Liebigs Ann./Recueil 1997, 637. (b)Borman, S. Chem. Eng. News 1996, 74(45), 37.

[0294] (2) (a) Francis, M. B.; Finney, N. S.; Jacobsen, E. N. J. Am.Chem. Soc. 1996, 118, 8983. (b) Burger, M. T.; Still, W. C. J. Org.Chem. 1995, 60, 7382. (c) Malin, R.; Steinbrecher, R.; Jannsen, J.;Semmler, W.; Noll, B.; Johannsen, B.; Frommel, C.; H hne, W.;Schneider-Mergener, J. J. Am. Chem. Soc. 1995, 117, 11821. (d) Hall, D.G.; Schultz, P. G. Tetrahedron Lett. 1997, 38, 7825. (e) Shibata, N.;Baldwin, J. E.; Wood, M. E. Biorr. Med. Chem. Lett. 1997, 7, 413.

[0295] (3) (a) Briceno, G.; Chang, H.; sun, X.; Schultz, P. G.; Xiang,X.-D. Science 1995, 270, 273. (b) Danielson, E.; Golden, J. H.;McFarland, E. W.; Reaves, C. M.; Weinberg, W. H.; Wu, X. D. Nature 1997,389, 944. (c) Brocchini, S.; James, K.; Tangpasuthadol, V.; Kohn, J. J.Am. Chem. Soc. 1997, 119, 4553. (d) Baker, B. E.; Kline, N. J.; Teado,P. J.; Natan, M. J. J. Am. Chem. Soc. 1996, 118, 8721.

[0296] (4) For recent reviews on strategies for the synthesis andevaluation of small-molecule libraries, see: (a) Hobbs DeWitt, S.;Czarnik, A. W. Acc. Chem. Res. 1996, 29, 114. (b) Thomson, L. A.;Ellman, J. A. Chem. Rev. 1996, 96, 555. (c) Armstrong, R. W.; Combs, A.P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,29, 123. (d) Still, W. C. Acc. Chem. Res. 1996, 29, 155. (e) Terret, N.K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron1995, 51, 8135.

[0297] (5) See, for example: (a) Combs, A. P.; Kapoor, T. M.; Feng, S.;Chen, J. K.; Daud_-Snow, L. F.; Schreiber, S. L. J. Am. Chem. Soc. 1996,118, 287. (b) Cheng, Y.; Suenaga, T.; Still, W. C. J. Am. Chem. Soc.1996, 118, 1813. (c) Liang, R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi,Y.; Sekanina, K.; Horan, N.; Gildersleeve, J.; Thompson, C.; Smith, A.;Biswas, K.; Still, W. C.; Kahne, D. Science 1996, 274, 1520.

[0298] (6) See, for example: Kick, E. K.; Roe, D. C.; Skillman, A. G.;Liu, G.; Ewing, T. J. A.; Sun, Y.; Kuntz, I. D.; Ellman, J. A. Chem.Biol. 1997, 4, 297.

[0299] (7) For related efforts, see: (a) Burgess, K.; Lim, H.-J.; Porte,A. M.; Sulikowski, G. A. Angew. Chem. Int. Ed. Engl. 1996, 35, 220. (b)Cole, M. B.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper,M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 1996, 35, 1668.Burgess and Sulikowski evaluated libraries of spatially-arrayed metalligand complexes prepared by combining a series of known ligands with aseries of metal ions. Snapper and Hoveyda developed a strategy for theoptimization of catalysts synthesized on solid support which they termed“positional scanning”, wherein each of the ligand components of thecatalyst is optimized in a serial manner. Unlike the combinatorialapproach in the present paper wherein every possible ligand permutationis prepared and evaluated, the Snapper-Hoveyda approach results in onlya small fraction of the possible ligands being prepared, and as aconsequence might miss particularly effective ligand combinations.Nonetheless, their approach has led to the same optimal catalyststructures regardless of the order in which the ligand components arevaried.

[0300] (8) (a) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett.1975, 1707. (b) Hayashi, M.; Inoue, T.; Miyamoto, Y.; Oguni, N.Tetrahedron 1994, 50, 4385. (c) Carreira, E. M.; Singer, R. A.; Lee, W.J. Am. Chem. Soc. 1994, 116, 8837. (d) Bolm, C.; Bienewald, F. Angew.Chem. Int. Ed. Engl. 1995, 34, 2641.

[0301] (9) Reactions were carried out in 1 mL glass test tubes. Detailsare provided in the Supporting Information.

[0302] (10) (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M.J. Am. Chem. Soc. 1996, 118, 4910. (b) In independent investigations, wehave recently identified A1-based asymmetric catalysts for the Streckerreaction: Sigman, M. S.; Jacobsen, E. N. submitted.

Supporting Information

[0303] General: 100-200 μm aminomethylated polystyrene (0.44 mmol/g) waspurchased form Novabiochem and rinsed with DMF, THF, and toluene beforeuse. Fmoc-amino acids were purchased from Advanced Chemtech and used asreceived. TMSCN was purchased from Aldrich and distilled before use.TBSCN was purchased from Aldrich and used as received.(R,R)-1,2-Diaminocyclohexane¹ and (R,R)-diphenyl-1,2-ethylenediamine²were resolved by literature methods. CP was synthesized by a literaturemethod.³ Salicylaldehydes were synthesized according to publishedprocedures.¹ For library 1 (linker/urea), the aminomethylatedpolystyrene was derivatized with 6-aminocaproic acid using procedures band c (below). All coupling reactions were carried out in fritted 1.5 mLor 10 mL disposable chromatography columns. Reactions were filtered uponcompletion and rinsed with DMF, THF, CH₂Cl₂ and toluene unless otherwiseindicated. The progress of all amino acid coupling reactions wasmonitored by the UV quantification of dibenzofulvene released from 2 mgresin samples upon Fmoc cleavage. Thiourea and urea formation weremonitored by IR for disappearance of isothiocyanate and p-nitrophenylcarbamate bands.

[0304] Solid Phase Urea Library Synthesis:

[0305] Synthesis Outline:

[0306] (a) Library split into appropriate number of vials. (b) 2.5 eqFmoc-amino acid, 2.5 eq HBTU, 5 eq DIPEA, 2.5 eq HOBT, DMF, 2 h. (c) 30%piperdine in DMF, 30 min. (d) 0.5 M p-nitrophenyl chlorofornate, 0.5 MDIPEA, THF/CH₂Cl₂ (1/1, v/v), 30 min (rinsed with THF and CH₂Cl₂ only).⁴(e) 0.5 M Diamine, TEA, DMF, 3 h. (f) aldehyde, DMF, 1 h.

[0307] Solid Phase Thiourea Library Synthesis:

[0308] Synthesis Outline:

[0309] (a) Library split into appropriate number of vials. (b) 2.5 eqFmoc-amino acid, 2.5 eq HBTU, 5 eq DIPEA, 2.5 eq HOBT, DMF, 2 h. (c) 30%piperdine in DMF, 30 min.

[0310] (d) 0.5 M thiocarbonyl diimidazole, THF, 30 min (rinsed with THFand CH₂Cl₂ only). (e) 0.5 M Diamine, TEA, DMF, 3 h. (f) aldehyde, DMF, 1h.

[0311] Formation of Solid Phase Metal Complexes:

[0312] Using Leu-CH-A as a representative library member, the resin wassuspended in a 0.1 M solution of the metal source and agitated for thelength of time specified in Table 1. The resin was rinsed with THF,CH₂Cl₂, toluene followed by drying under reduced pressure. Incorporationof metal was tested by staining with either 1-nitroso-2-naphthol (NNP)or pyrocatechol violet (PCV) (Table 1). TABLE 1 Conditions and stainingof metal insertions into Leu-CH-A. Metal Source Solvent (time) ColorStain (color) Zn(OTf)₂/2,6-lutidine THF (4 h) Light PCV (blue) yellowTi(OiPr)₄ Toluene (4 h) Yellow PCV (blue) Zr(OiPr)₄ THF (12 h) YellowPCV (red) Yb(OTf)₃/2,6-lutidine THF (12 h) Yellow PCV (red) Fe(acac)₃THF (12 h) Green PCV (red) Rh(acac)₃ THF (12 h) Purple No testCo(OAc)₂/2,6-lutidine EtOH (12 h) Brown NNP (orange) Cu(acac)₂ THF (4 h)Green/ PCV (green) blue Gd(OTf)₃/2,6-lutidine 10% MeOH/THF (5 h) YellowPCV (red) Nd(OTf)₃/2,6-lutidine 10% MeOH/THF (5 h) Yellow PCV (red)MnCl₂/2,6-lutidine 10% MeOH/THF (5 h) brown PCV (green)

[0313] Screening of the Strecker Reaction:

[0314] In 500 μL test tubes, 1 mg of resin (one library member per vial,4.4 mol%), 50 μL of a 200 mM solution of imine in toluene and 50 μL of a250 mM solution of TBSCN in toluene were combined. Each vial was sealedwith a rubber septum and agitated for 15 h. After this time, a 20 μLaliquot was quenched in a 400 μL solution of trifluoroacetic anhydride(100 mM) in dichloroethane. Conversions and enantioselectivities weredetermined by autosampling GC equipped with a 20 m×0.25 mm γ-TA chiralcolumn (Advanced Seperations Technologies inc., 37 Leslie Ct, P.O. Box297, Whippany, N.J. 07981, 110° C. isothermal, 25 min).

[0315] Synthesis of Solution Phase Catalyst:

[0316] (Benzyl-t-Leu):

[0317] To a solution of 500 mg of Fmoc-tert-Leucine (1.41 mmol) and 0.54mL of DIPEA (3.11 mmol, 2.2 equiv) in acetonitrile, 590 mg of HBTU (1.55nunol, 1.1 equiv) was added. After 1 min, 309 μL of benzyl amine (2.82mmol, 2.0 equiv) was added and the reaction stirred for 30 min. Themixture was partitioned between CHCl₃ (50 mL) and H₂O (50 mL). Theorganic phase was washed with H₂O (2×50 mL), dried over Na₂SO₄, andconcentrated in vacuo The resulting residue was filtered through a shortplug of silica eluting with 4% MeOH/CH₂Cl₂. The solvent was removed invacuo and the residue was dissolved in 10 mL 1:1 piperdine/MeOH, stirredfor 30 min and partitioned between 50 mL of CHC₃ and 25 mL H₂O. Theorganic phase was washed with H₂O (25 mL), dried over Na₂SO₄ andconcentrated in vacuo. Purification by silica gel chromatography (5%MeOH/CH₂Cl₂) afforded 242 mg of a white solid (78% yield, 2 steps): mp53-54° C.; IR (KBr) 3303, 1650 cm^(−1.), ¹H NMR (400 MHz, CDCl₃)δ7.33(m, 5H), 7.05 (s, 1H), 4.45 (d, J =0.9 Hz, 1H), 4.43 (d, J=0.9 Hz, 1H),3.14 (s, 1H), 1.41 (s, 2H), 1.01 (s, 9H); ¹³C NMR {¹H} (100 MHz,CDCl₃)δ173.4, 138.5, 128.5, 127.8, 127.3, 64.3, 43.0, 34.1, 26.7; HRMS(M+H) calcd 221.1654, obsd 221.1658.

[0318] Benzyl-t-Leu-CH-3(1):

[0319] To a 0° C. solution of 45 mg of thiocarbonyl diimidazole (0.255mmol, 1.1 equiv) in 2 mL of CH₂Cl₂ was added a precooled solution ofBenzyl-t-Leu (51 mg, 0.232 mmol) in 2 mL of CH₂Cl₂ over 1 min. After 10min, the solution was filtered through a short plug of silica, elutingwith CH₂Cl₂. The solvent was concentrated to ca. 2 mL and added slowlyto a stirring solution of (R,R)-1,2-diaminocyclohexane (132 mg, 1.16mmol, 5 eq) in 1 mL of CH₂Cl₂. After 30 min, the reaction mixture waspartitioned between CH₂Cl₂ (20 mL) and H₂O (20 mL). The organic layerwas washed with H₂O (2×20 mL), dried over Na₂SO₄ and concentrated byreduced pressure. A NMR of the resulting residue showed a mixture of twomain products. This mixture was dissolved in 2 mL of MeOH, treated with24 mg of 3 (0.114 mmol) and allowed to stir for 1 hr. The solvent wasremoved in vacuo and the resulting residue was purified by silica gelchromatography (1% MeOH/CH₂Cl₂) affording a yellow solid in 18% overallyield (3 steps): recrystallized from benzene/hexane (1:3); mp 115° C.(dec); IR (KBr) 330, 2942, 1649, 1535 cm⁻¹; ¹H NMR (400 MHz,CDCI₃)δ13.80 (s, 1H), 8.18 (s, 1H), 7.20 (d, J=2.9 Hz, 1H), 7.05 (m,4H), 6.99 (m, 1H), 6.85 (br, 1H), 6.68 (d, J =2.9 Hz, 1H), 6.20 (br,1H), 5.56(br, 1H), 5.01 (br, 1H), 4.29 (dd, J=6.4, 15 Hz, 1H), 4.07 (br,1H), 3.87 (dd, J=5.1 HZ, 1H), 3.50 (br, 3H), 2.99 (br, 1H), 1.91 (s,1H), 1.58 (s, 9H), 1.58-1.01 (m, SH), 0.97 (s, 9H); ³C NMR {¹H} (100MHz, CDCl₃)δ170.7, 165.7, 154.8, 151.2, 138.9, 137.6, 128.7, 127.9,127.8, 127.6, 118.6, 118.0, 111.8, 77.2, 66.5, 57.1, 55.9, 43.6, 35.0,34.8, 32.9, 31.1, 29.3, 26.8, 24.0, 23.4; HRMS m/z (M+Na) calcd589.3188, obsd 589.3183.

[0320] Solution Phase Catalyst Screening:

[0321] In a flamed dried 10 mL round bottom flask, 1 (1.8 mg, 3.5 μmol,2 mol %), imine (25 mg, 0.17 mmol) and 0.7 mL of toluene were combined.The reaction was cooled to −78° C. and 125 μl of a 2.8 M solution of HCN(2 equiv) in toluene was added. After stirring for 24 h, the reactionwas quenched with TFAA (2 equiv) and warmed to ambient temperature. Thesolvent was removed in vacuo and the resulting was purified as andanalyzed as described below.

[0322] (10 a):

[0323] Product was obtained in 78% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 91% eeby Chiral GC analysis (γ-TA, 110° C. isothermal, tr(maj or)=21.7 min,tr(minor)=25 24.5 min); IR (thin film) 2936, 2249, 1701cm⁻¹; ¹H NMR (400MHz, CDCl₃)δ7.45 (m, 5H), 6.65 (s, 1H), 5.66 (m, 1H), 5.19 (d, J=10.2Hz, 1H), 5.13 (d, J=17.0 Hz, 1H) 4.15 (dd, J=4.7, 17.0 Hz, 1H), 3.91(dd, J=6.0, 17.0 Hz, 1H); ¹³C NMR {¹H} (100 MHz, CDCl₃)δ157.9 (q, J=38Hz),131.1, 130.1, 130.0, 129.4, 127.8, 120.3, 117.5 (q, J=288 Hz),115.2, 49.8, 48.6; HRMS m/z (M+NH₄ ⁺) calcd 286.1167, obsd 286.1163.

[0324] (10 b):

[0325] Product was obtained in 92% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in

[0326]70% ee by Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1mL./min, t_(r)(major)=9.7 min, tr(minor)=11.5 min; IR (thin film) 2940,1701, 1613 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ7.36 (d, J=8.6 Hz, 2H), 6.94(d, J=8.6 Hz, 2H), 6.57 (s, 1H), 5.65 (m, 1H), 5.19 (d, J=10.2 Hz, 1H),5.14 (d, J=17.2 Hz, 1H), 4.15 (dd, J=4.2, 17.0 Hz, 1H), 3.87 (dd, J=6.2,17.0 Hz, 1H), 3.83 (s, 3H); ¹³C NMR {¹H} (100 MHz, CDCl₃)δ160.9, 157.8(q, J=38 Hz), 131.4, 129.5, 121.9, 120.1, 117.5 (q, 10 J=288 Hz), 115.6,114.8, 55.5, 49.4, 48.3; HRMS m/z (M⁺) calcd 298.0929, obsd 298.0936.

[0327] (10 c):

[0328] Product was obtained in 65% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 86% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 mL./min,tr(major)=6.2 min, tr(minor)=8.1 min); IR (thin film) 2936, 1701 cm⁻¹;¹H NMR (400 MHz, CDCl₃)δ7.56 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H),6.52 (s, 1H), 5.65 (m, 1H), 5.21 (d ,J=10.2 Hz, 1H), 5.15 (d, J=17.1 Hz,1H), 4.15 (dd, J=5.5, 17.0 Hz, 1H), 3.92 (dd, J=6.3, 17.0 Hz, 1H); ¹³CNMR {¹H} (100 MHz, CDCl₃)δ157.7, 132.7, 131.0, 129.5, 124.5,120.8,117.4, 114.8, 114.5, 49.6, 49.0; HRMS m/z (M⁺) calcd 345.9929,obsd 345.9931.

[0329] (10 d):

[0330] Product was obtained in 88% yield as a white solid afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 88% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 mL./min,t,(major)=7.0 min, t,(minor)=8.4 min). mp 72-73° C.; IR (thin film)3061, 2934, 1701 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ8.06 (s, 1H), 7.90 (m,3H), 7.59 (m, 2H), 7.37 (m, 1H) 6.85 (s, 1H), 5.69 (m, 1H), 5.17 (d,J=10.4 Hz, 1H), 5.12 (d, J=17.2 Hz, 1H), 4.20 (dd, J=4.9, 17.0 Hz, 1H),3.50 (dd, J=6.5, 17.0 Hz, 1H); ¹³C NMR {¹H} (100 MHz, CDCl₁₃)δ157.9 (q,J=38 Hz), 133.6, 132.9, 131.2, 129.8, 128.3, 128.1, 127.9, 127.7, 127.4,124.2, 120.4, 117.6 (q, J=287 Hz), 115.4, 114.7, 50.0, 48.6; HRMS m/z(M⁺) calcd 318.0980, obsd 318.0974.

[0331] (10 e):

[0332] Product was obtained in 70% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 85% eeby Chiral GC analysis (γ-TA, 112° C. isothermal, t_(r)(major)=4.0 min,t_(r)(minor)=6.0 min); IR(thin film) 2972, 1705cm⁻¹; ¹H NMR (400 MHz,CDCl₃)δ5.87 (m, 1H), 5.33 (d, J=10.4 Hz, 1H), 5.25 (d, J=17.2 Hz, 1H),4.25 (s(br), 2H), 1.16 (s, 9H); ¹³C NMR {¹H} (100 MHz, CDCl₃)δ157.5(J=37 Hz), 132.0, 119.0, 117.4 (q, J=286 Hz), 115.3, 56.7, 40.5, 38.1,26.9; HRMS m/z (M+NH₄ ⁺) calcd 266.1480, obsd 266.1481.

[0333] (10 f):

[0334] Product was obtained in 77% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 83% eeby Chiral GC analysis (γ-TA, 120° C. isothermal, t_(r)(major)=13.6 min,t_(r)(minor)=15.6 min); IR (thin film) 2936, 2859, 1704 cm⁻¹; ¹H NMR(400 MHz, CDCl₃)δ5.85 (m, 1H), 5.38 (d , J=15.7 Hz, 1H), 5.35 (d, J=9.8Hz, 1H), 4.65 (d, J=10.6 Hz, 1H), 4.26 (dd, J=4.9, 16.9 Hz, 1H) 4.26(dd, J=6.9, 16.9 Hz, 1H), 2.09 (m, 2H), 1.84-1.60 (m, 4H), 1.40-0.85 (m,5H); ^(—)C NMR {¹H} (100 MHz, CDCl₃)δ157.8 (J=37 Hz), 131.6, 120.6,117.4 (q, J=286 Hz), 115.9, 53.6, 50.4, 38.3, 30.0, 28.9, 25.7, 25.3,25.1; HRMS m/z (M+NH₄ ⁺) calcd 292.1637, obsd 292.1625.

[0335] Absolute Configuration Determination:

[0336] Racemic and (R)-phenylglycine were converted to their methylesters⁵ and allylated with allyl acetate (Pd-catalyzed).⁶ Analysis ofthe trifluoroacetamide of the product by Chiral GC (γ-TA isothermal 112°C.) gave retention times of 36.0 (R) and 37.62 (S). Asymme tric Streckerreaction product was hydrolyzed to the allyl amino acid methyl ester.Chiral GC analysis showed the major enantiomer to be (S). The othercompounds were assigned by analogy to be (S) amino nitriles.

[0337] IR (thin film) 3338, 1738 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ7.34 (m,5H), 5.88 (ddd, J=6.1, 10.1, 17.2 Hz, 1H), 5.17 (dd, J=1.6, 17.2 Hz,1H), 5.12 (dd,J=1.3, 10.1 Hz, 1H)), 4.41 (s, 1H), 3.69 (s, 3H), 3.21(dd, J=6.1, 1.0 Hz, 1H), 3.19 (dd, J=6.1, 1.0 Hz, 1H); ¹³C NMR {¹H} (100MHz, CDCl₃)δ173.3, 137.9, 135.9, 128.77,128.0, 127.4, 116.7, 64.3, 52.1,50.0; HRMS m/z (M+H) calcd 206.1181, obsvd 206.1174.

[0338] (1) Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.;Zepp, C. M. J. Org. Chem. 1994, 59, 1939.

[0339] (2) Pikul, S.; Corey, E. J. Org. Synth. 71, 22.

[0340] (3) Reddy, D. R.; Thorton, E. R. J. Chem. Soc. Commun. 1992, 172.

[0341] (4) (a) Hutchins, S. M.; Chapman, K. T. Tetrahdron Lett., 1994,35, 4055. (b) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett., 1995,36, 2583.

[0342] (5) Bodanszky, M.; Bodanszky, A. The Practice of PeptideSynthesis Springer-Verlag: New York, 1994,p30.

[0343] (6) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. Japan1972,45,230.

[0344] All of the references and publications cited herein are herebyincorporated by reference.

Equivalents

[0345] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, numerous equivalents to thespecific polypeptides, nucleic acids, methods, assays and reagentsdescribed herein. Such equivalents are considered to be within the scopeof this invention.

We claim:
 1. A parallel, combinatorial method for the discovery andoptimization of novel catalysts for chemical transformations,comprising: (a) chemically synthesizing a variegated library ofpotential catalysts; and (b) screening the library of potentialcatalysts to identify those members that catalyze the transformation ofinterest.
 2. The method of claim 1, wherein the potential catalystscomprise a natural or unnatural amino acid.
 3. The method of claim 1,wherein the library comprises a catalyst that catalyzes astereoselective reaction.
 4. The method of claim 1, wherein the librarycomprises a catalyst that catalyzes a chemoselective and/orregioselective reaction.
 5. The method of claim 1, wherein the potentialcatalysts comprise a cyclic moiety selected from the group consisting ofacridarsine, acridine, anthracene, arsindole, arsinoline, azepane,benzene, carbazole, carboline, chromene, cinnoline, furan, furazan,hexahydropyridazine, hexahydropyrimidine, imidazole, indane, indazole,indole, indolizine, isoarsindole, isobenzofuran, isochromene, isoindole,isophosphindole, isophosphinoline, isoquinoline, isorasinoline,isothiazole, isoxazole, morpholine, naphthalene, naphthyridine, oxazole,oxolane, perimidine, phenanthrene, phenanthridine, phenanthroline,phenarsazine, phenazine, phenomercurazine, phenomercurin,phenophosphazine, phenoselenazine, phenotellurazine, phenothiarsine,phenoxantimonin, phenoxaphosphine, phenoxarsine, phenoxaselenin,phenoxatellurin, phenothiazine, phenoxathiin, phenoxazine,phosphanthene, phosphindole, phosphinoline, phthalazine, piperazine,piperazine, piperidine, piperidine, pteridine, purine, pyran, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrolidine, pyrrolidine,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,selenanthrene, selenophene, tellurophene, tetrahydrofuran,tetrahydrothiophene, thianthrene, thiazole, thiolane, thiophene andxanthene.
 6. The method of claim 1, wherein the potential catalystscomprise a bicyclo[x.y.z]alkane, where x, y, and z are eachindependently integers greater than or equal to zero.
 7. The method ofclaim 1, wherein the potential catalysts comprise an asymmetric center.8. The method of claim 1, wherein the library of potential catalystscomprises a catalyst that is not superimposable on its mirror image. 9.The method of claim 1, wherein the library comprises at least onehundred potential catalysts.
 10. The method of claim 9, wherein thelibrary comprises at least one thousand potential catalysts.
 11. Themethod of claim 10, wherein the library comprises at least ten thousandpotential catalysts.
 12. The method of claim 1, wherein the potentialcatalysts comprise a saccharide or oligosaccharide.
 13. The method ofclaim 12, wherein the saccharide, or oligosaccharide, consists ofpentose sugars, hexose sugars, pentose azasugars, and/or hexoseazasugars.
 14. The method of any of claims 1-13, wherein the library issynthesized on a solid support.
 15. The method of any of claims 1-13,wherein the library is synthesized in solution.
 16. The method of claim1, wherein a selected catalyst is used as the lead structure for asecond library of potential catalysts; said second library of potentialcatalysts is screened to identify those members that catalyze thetransformation of interest; at least one of the members of the secondlibrary being an improved catalyst for the transformation of interestrelative to the catalyst from the first library.
 17. The method of claim16, wherein the described process is reiterated between one and tenadditional times to provide at least one improved catalyst for thetransformation of interest.
 18. The method of claims 1, 16 or 17,wherein a selected catalyst catalyzes a transformation selected from theset comprising kinetic resolutions, regioselective reactions,chemoselective reactions, diastereoselective reactions, stereoselectivereactions, functional group interconversions, hydrogenations,oxidations, reductions, resolutions of racemic mixtures, cycloadditions,sigmatropic rearrangements, electrocyclic reactions, ring-openings,carbonyl additions, carbonyl reductions, olefin additions, olefinreductions, imine additions, imine reductions, olefin epoxidations,olefin aziridinations, carbon-carbon bond formations, carbon-heteroatombond formations, and heteroatom-heteroatom bond formations.
 19. Themethod of claim 1, 16, or 17, wherein the catalysts are selected basedon the observation of a detectable event.
 20. The method of claim 19,wherein the detectable event is a member of the set comprising theevolution of a gas, the emission of a photon, and the formation of aprecipitate.
 21. A library of potential catalysts, and the individualmembers thereof, having the following general structure:

wherein the sphere represents a solid support; Linker₁ and Linker₂ areindependently selected from the group consisting of difunctionalmolecules with or without sidechains and/or stereocenters; amino acidrepresents a natural or unnatural amino acid; and the catalytic moietyis selected from the set comprising the catalytically-active portions ofknown catalysts.
 22. The library and individual catalysts of claim 21,wherein Linker₁ and Linker₂ are independently selected from the setcomprising diamines, diols, amino alcohols, and diacids; and thecatalytic moiety is selected from the set comprising salenates,porphyrins, Schiff base-containing moieties, diketopiperazines,oligoamines, oligoalcohols, amino alcohols, oligopeptides, andoligonucleotides.
 23. The library and individual catalysts of claim 22,wherein the catalytic moiety is mono-, di-, tri-, or tetra-dentate withrespect to a substrate.
 24. The library of claims 21, 22 or 23, whereinthe library comprises at least one hundred potential catalysts.
 25. Thelibrary of claims 21, 22 or 23, wherein the library comprises at leastone thousand potential catalysts.
 26. The library of claims 21, 22 or23, wherein the library comprises at least ten thousand potentialcatalysts.
 27. The library and individual catalysts of claims 21, 22 or23, wherein a selected catalyst is used as the lead structure for asecond library of potential catalysts; said second library of potentialcatalysts is screened to identify those members that catalyze thetransformation of interest; at least one of the members of the secondlibrary being an improved catalyst for the transformation of interestrelative to the catalyst from the first library.
 28. The library andindividual catalysts of claim 27, wherein the described process isreiterated between one and ten additional times to provide at least oneimproved catalyst for the transformation of interest.
 29. The method ofclaims 27 or 28, wherein a selected catalyst catalyzes a transformationselected from the set comprising kinetic resolutions, regioselectivereactions, chemoselective reactions, diastereoselective reactions,stereoselective reactions, functional group interconversions,hydrogenations, oxidations, reductions, resolutions of racemic mixtures,cycloadditions, sigmatropic rearrangements, electrocyclic reactions,ring-openings, carbonyl additions, carbonyl reductions, olefinadditions, olefin reductions, imine additions, imine reductions, olefmepoxidations, olefin aziridinations, carbon-carbon bond formations,carbon-heteroatom bond formations, and heteroatom-heteroatom bondformations.
 30. The method of claims 27 or 28, wherein the catalysts areselected based on the observation of a detectable event.
 31. The methodof claim 30, wherein the detectable event is a member of the setcomprising the evolution of a gas, the emission of a photon, and theformation of a precipitate.
 32. A parallel, combinatorial method for thediscovery and optimization of catalysts for a transformation from theset comprising the Strecker reaction, the aldol addition, the aldolcondensation, the Michael addition, the Claisen rearrangement, the Coperearrangement, the dihydroxylation of olefins, the epoxidation ofolefins, the aziridination of olefins, the Darzen's condensation, theDiels-Alder reaction, the hetero-Diels-Alder reaction, the ene reaction,the hetero-ene reaction, the Wittig rearrangement, the Nazarovcyclization, the asymmetric addition of Grignard reagents tocarbon-heteroatom π-bonds, the asymmetric addition of organolithiumreagents to carbon-heteroatom π-bonds, the asymmetric Robinsonannulation, and the Simmons-Smith reaction.
 33. A catalyst representedby the following general structure:

wherein B represents a monocyclic or polycyclic group; C₁, C₂ and C₃each represent chiral carbon atoms; X represents O, S or NH; Jrepresents a linker group including at least one functional groupcapable of acting as a hydrogen bond donor; R₁₀₃ represents either ahydrogen bond donor, a Lewis basic group, or a group with bothcharacteristics; R₁₀₄ represents a sterically bulky, aliphatic orcycloaliphatic substituent of up to 20 carbons (preferably 2-10); R₁₀₅is absent, or represents one or more additional substituents of Bselected from the group consisting of alkyl, alkenyl, alkynyl, acyl,thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R_(80;) and R₁₀₆and R₁₀₇ each independently represent alkyl, alkenyl, alkynyl, acyl,thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or -( CH₂)_(m)—R_(80,) or R₁₀₆and R₁₀₇ taken together with C₂ and C₃ form a ring having from 4 to 8atoms in the ring; R₁₀₈ and R₁₀₉ each independently represent an alkyl,represent alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal,ketal, aryl, heteroaryl, aziridine, carbarnate, epoxide, hydroxamicacid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea,thiourea, or —(CH₂)_(m)—R₈₀, with the proviso that R₁₀₈ and (C(X)R₁₀₉)are not identical (this proviso is implied by the aforementionedchirality of C₁); R₈₀ represents an unsubstituted or substituted aryl, acycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and m is aninteger in the range 0 to 8 inclusive.
 34. A catalyst according to claim33, wherein X is S or O.
 35. A catalyst according to claim 33, whereinR₁₀₃ is —NH₂, —OH, or —SH, or a lower alkyl group substituted thereby.36. A catalyst according to claim 33, wherein R₁₀₄ is attached to B at aposition both ortho to R₁₀₃, and meta to the imine substituent on B. 37.A catalyst according to claim 33, wherein R₁₀₄ is a lower alkyl oralkoxyl group.
 38. A catalyst according to claim 33, wherein R₁₀₆ andR₁₀₇ are C₃-C₈ alkyl groups, or, together with C₂ and C₃ form a ringhaving from 4 to 8 atoms in the ring.
 39. A catalyst according to claim33, wherein J is represented by —NH—Y—NH—; Y is selected from the groupconsisting of

Q₁ represents S or O; and R₄₆ represents hydrogen, a lower alkyl or anaryl.
 40. A catalyst according to claim 39, wherein Y is —C(=Q₁)—; andQ₁ is O or S.
 41. A catalyst according to claim 33, wherein R₁₀₈represents an alkyl, heteroalkyl, aryl or heteroaryl group.
 42. Acatalyst according to claim 33, 39, or 40, wherein R₁₀₈ represents aside-chain of a naturally occurring a-amino acid or analog thereof. 43.A catalyst according to claim 42, wherein R₁₀₉ represents an aminogroup.
 44. A catalyst represented by the following general structure:

wherein A represents a monocyclic or polycyclic group; B represents amonocyclic or polycyclic group; C₁ represents a chiral carbon atom; Xrepresents O, S or NH; R₁₀₃ represents either a hydrogen bond donor, aLewis basic group, or a group with both characteristics; R₁₀₄ representsa sterically bulky, aliphatic or cycloaliphatic substituent of up to 20carbons; R₁₀₅ is absent, or represents one or more additionalsubstituents of B selected from the group consisting of alkyl, alkenyl,alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl,aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime,sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R_(80;) and R₁₀₈ and R₁₀₉ each independently represent analkyl, represent alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio,imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal,ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R_(80,) with the proviso that R₁₀₈ and (C(X)R₁₀₉) are notidentical (this proviso is implied by the aforementioned chirality ofC₁); R₁₁₀ is absent, or represents one or more additional substituentsof A selected from the group consisting of alkyl, alkenyl, alkynyl,acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate,phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R_(80.) R₈₀represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; and m is an integer in therange 0 to 8 inclusive.
 45. A catalyst according to claim 44, wherein Ais a cycloalkyl having 5, 6 or 7 carbons in the ring structure.
 46. Acatalyst represented by the following general formula:

wherein X represents, independently for each occurrence, O, S, or NR; R,R₁, R₂, and R₃ represent, independently for each occurrence, H, alkyl,aryl, heteroalkyl, or heteroaryl; R₄ represents H, alkyl, heteroalkyl,aryl, heteroaryl, fornyl, or acyl; R₂ is absent or occurs no more than 4times; and n is an integer selected from the range 0 to 2 inclusive. 47.A catalyst according to claim 46, wherein X represents, independentlyfor each occurrence, O or S; R, R₁, R₂, and R₃ represent, independentlyfor each occurrence, H, alkyl, aryl, heteroalkyl, or heteroaryl; R₄represents alkyl, heteroalkyl, aryl, or heteroaryl; R₂ is absent; and nis an integer selected from the range 0 to 2 inclusive.
 48. A catalystaccording to claim 47, wherein X represents, independently for eachoccurrence, O or S; R, R₁, R₂, and R₃ represent, independently for eachoccurrence, H, alkyl, aryl, heteroalkyl, or heteroaryl; R₄ representsformyl or acyl; R₂ is absent; and n is an integer selected from therange 0 to 2 inclusive.
 49. A catalyst according to claim 33, 44, or 46,wherein said catalyst catalyzes an enantioselective ordiastereoselective transformation that produces a product with anenantiomeric or diastereomeric excess, respectively, of at least 75%.50. A catalyst according to claim 33, 44, or 46, wherein said catalystcatalyzes an enantioselective or diastereoselective transformation thatproduces a product with an enantiomeric or diastereomeric excess,respectively, of at least 80%.
 51. A catalyst according to claim 33, 44,or 46, wherein said catalyst catalyzes an enantioselective ordiastereoselective transformation that produces a product with anenantiomeric or diastereomeric excess, respectively, of at least 85%.52. A catalyst according to claim 33, 44, or 46, wherein said catalystcatalyzes an enantioselective or diastereoselective transformation thatproduces a product with an enantiomeric or diastereomeric excess,respectively, of at least 90%.
 53. A catalyst according to claim 33, 44,or 46, wherein said catalyst catalyzes an enantioselective ordiastereoselective transformation that produces a product with anenantiomeric or diastereomeric excess, respectively, of at least 95%.54. A catalyst according to claim 33, 44, or 46, wherein said catalystcatalyzes an enantioselective or diastereoselective transformation thatproduces a product with an enantiomeric or diastereomeric excess,respectively, of at least 98%.